(1999; 168 pages) [Spanish]
3. Self-inspection and quality audits
An inspection team consisting of appropriate personnel (e.g. auditors, engineers, laboratory analysts, purchasing agents, computer experts) should participate in inspections. The operational limitations and validation of the critical processing steps of a production process should be examined, to make sure that the manufacturer is taking adequate steps to check that the process works consistently.
The excipient's end use should be identified and considered during inspection of excipient manufacturers. It is particularly important to know whether the excipient is a direct or indirect component of a drug dosage form; whether the excipient will be used in the preparation of a sterile dosage form: and whether the excipient is presented as pyrogen/endotoxin free. The excipient manufacturer is responsible for ensuring that excipients are pyrogen free if the manufacturer makes such a representation in specifications, labels or a drug master file.
A good starting point for an excipient plant inspection is a review of the following areas:
• Non-conformance, such as the rejection of a batch not complying with specifications, return of a product by a customer, or recall of a product. The cause of non-conformance should have been determined by the manufacturer, a report of the investigation prepared, and subsequent corrective action initiated and documented. Records and documents should be reviewed to ensure that such non-conformance is not the result of a poorly developed or inconsistent process.
• Complaint files. Customers may report some aspects of product attributes that are not entirely suitable for their use. These may be caused by impurities or inconsistencies in the excipient manufacturing process.
• Change control documentation.
• Master formula and batch production records. Frequent revisions may reveal problems in the production process.
• Specifications for the presence of unreacted intermediates and solvent residues in the finished excipient.
• Storage areas for rejected products.
In evaluating the adequacy of measures taken to preclude contamination of materials in the process, it is appropriate to consider the following factors:
• Type of system (e.g. open or closed). "Closed" systems in chemical plants are often not closed when they are being charged and/or when the final product is being removed. Also, the same reaction vessels are sometimes used for different reactions.
• Form of the material (e.g. wet or dry).
• Stage of processing and use of the equipment and/or area (e.g. multipurpose or dedicated).
Other factors that should be considered in evaluating an excipient plant are:
• Degree of exposure of the material to adverse environmental conditions.
• Relative ease and thoroughness of clean-up.
• Sterile versus non-sterile operations.