The quality control (QC) laboratory presents a different type of issue. Although governed under 21 CFR, Parts 211, 600 and 820, the regulations should not be confused with 21 CFR, Part 58. Part 58 is Good Laboratory Practices and refers to preclinical testing facilities. The QC laboratories of a manufacturing facility are regulated under GMP.
In quality control, one looks for the qualification of equipment, as well as in manufacturing, and the validation of the methods that are used. For example, HPLC and GC-MS are common tools for analysis. Generally, when the equipment is qualified, an installer does it from the company that furnishes the equipment.
However, the pages of the qualification manual are signed-off by someone from the company who theoretically witnesses what is occurring. A point of contention is that too many times the company person signing does not have the training and/or experience and/or education to sign-off properly (21 CFR 211.25). This indicates a control issue. The inspector also looks in the QC laboratory for how refrigerators are monitored and qualified and if reagents and standards are stored properly.
Throughout the inspection it is part of the FDA's mission to determine whether the company individuals have met the requirements of 21 CFR, Part 25 as noted above. Do they have the training and/or experience and/or education to perform their assigned tasks? The inspector can look at training records as well as the respective curriculum vitae to establish this.
It has been our experience that the FDA inspectors spend much more time with documentation than they do with the actual operations. This may be for two reasons. The first is that a state of control can be readily established through the documentation and handling investigations, root cause analysis, and corrective and preventive actions.
Secondly, FDA inspectors do not normally have the operating experience or do not come out of industry and therefore are not specialized enough to look at certain areas, especially in biologics, which is a highly complex production. However, we have had experience with some FDA inspectors who are very knowledgeable about manufacturing.
With respect to documentation, it is our recommendation that the following items be looked at within the company to prepare for an FDA inspection: quality assurance manual, master records, batch records, validations and qualifications, complaint handling, and corrective and preventive actions.
The quality assurance manual represents the policies of the company. It is important that these policies are followed. When the FDA requests to see the manual, they will be looking for supporting evidence or verification that the policies are being carried out.
The master record, as defined by the Agency, is the "recipe" for making the product. This is a complete set of instructions including quality control as well as production, packaging, and labeling. The FDA may compare the master record against representative batch or history records to make certain that the master record is being followed. Therefore, unless pages are duplicated, the history record or batch record should never exceed the size of the master record. This would indicate that there is a problem.
In addition, the Agency will be looking for deviations, out-of-specification results (OOS) or non-conformances and how these were managed. For example, does the company know the difference between an OOS and a non-conformance? Although there are several definitions, the one that we like to use is that an out-of-specification result is a failed result found in quality control.
However, it is not known whether this is an error due to the operator, the equipment, or the reagents. If, after following a rigorous investigation in quality control, one cannot assign a cause, then we have a situation where retesting or resampling may occur under certain well-defined consistent conditions. If, in fact, the product still fails, then we have a true nonconformance.