November 15, 2005 (Vol. 25, No. 20)

Preparation, Honesty, and Thorough Documentation Are Required to Pass

FDA inspections cause fear among some and apprehension amongst others. Such inspections often result in a disruption of activities and may result in a negative action taken by the federal government. These actions can result in seizure, a consent decree with financial penalties, or jail, especially if injury or death occurs.

The FDA conducts inspections for several reasons. The first is a Pre-Approval Inspection (PAI) after submission of a marketing application, such as a New Drug Application, Biologic License Application, or Pre-Market Approval Application has been filed. The second is part of a routine inspection program of all regulated facilities.

There is also a third reason for the FDA to conduct inspections. This may be “for cause.” FDA for-cause inspections are those where a series of adverse events may have occurred that have been reported to the FDA. In addition, prior inspections may have indicated poor quality. This can also result in a for-cause inspection.

Standard Operating Procedures (SOPs) on how to deal with FDA inspections should be prepared and instituted before an FDA inspector appears at the door. All company employees must know what to do and how to act. The inspector should never be left alone. Questions should be answered in an honest, straightforward way. Lawyers, of which I am not one, will usually say “don’t answer more than what is requested.” This may require less than a satisfactory answer.

In my experience with the Agency, which covers 30 years, I’ve found that a candid, honest answer is the best approach with an FDA inspector.

If the inspection is not for cause, it is not an adversarial proceeding and should not be treated as such. During the course of the inspection, the questions that are asked by the inspector should be answered. If the answer is not known, say “I don’t know the answer but the information will be furnished either later during the inspection or at a future time.”

Unless something is in progress, such as the development of a standard operating procedure or a validation procedure, don’t answer by saying “it is in progress” because then you will need to furnish proof. If there is a draft item, present the draft to the FDA inspector. The rule of thumb is “if it’s not in writing it doesn’t exist.”

Although it may not need mentioning for some, do not, under any circumstances, bend or fracture the truth to an FDA inspector. We are all familiar with Martha Stewart and the reason she was jailed: lying to a federal agency. When the FDA adjudicates, it turns the proceedings over to the justice department for administration.

Method of Inspection

For the past few years, the agency has been altering its method of inspection. On the surface it appears that somehow this improves the quality and quantity of the inspection. It is this author’s observation and commentary that this is not necessarily so.

It is my belief that the method changes were due to budget considerations, under funding, and lack of manpower. Switching one method of inspection to the Quality System Inspection Technique still establishes whether the organization is in a state of control. It is not clear how this improves compliance.

Described below are many items that should be in place before an FDA inspection occurs. They are divided into the facilities inspection and the documentation review and inspection.

Facility Inspection

The inspection of the facility begins where the regulated item or its components enter the facility’s receiving department, is quarantined, segregated, and sampled. The inspector then determines how the item is accepted into the warehouse. The process is followed by staging of the goods for manufacturing.

The inspection continues by observing manufacturing, filling or assembly, and, depending upon whether it is a device or a drug, packaging, segregation, final testing and approval, and shipping. As part of the facility inspection, the quality control laboratory is examined.

If appropriate labeling, segregation, quarantine, sampling, and storage of material are accomplished in the warehouse, there should be little difficulty with that part of the inspection. One should also keep in mind that substances that are regulated are generally in a controlled environment, such as for temperature and humidity, and all activities should be logged and managed under SOPs. Thermometers and humidity devices should also be appropriately calibrated on a routine basis.

The staging area is where all items are prepared in the right quantities and are ready for use in the actual manufacturing process. The manufacturing facility may consist of bio-reactors, blenders, chemical reactors, and plastic extrusion devices. These need to be managed in a controlled environment where contamination is minimized, if not eliminated.

Clean rooms need to be under constant testing for both live and other particulates, which define the quality of the clean room. The clean room must be qualified prior to being placed in service. Gowning procedures, entering into a clean room, and training of personnel are critical.

Handling of the product so as not to contaminate and reduce its purity or potency is observed by the FDA inspector. Points of testing and sampling and how they are performed, recorded, and managed also indicate a state of control.

When the product is filled or packaged, is it done after line clearance? Items present that do not belong on the line are a sign of lack of control. Labeling must be kept under lock and key and reconciled according to the regulations. These are all basic items, and when placed into practice, indicate Good Manufacturing Practices.

QC Laboratory

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.

Warning Letters

When one examines the FDA warning letters, which are now found on the FDA website, one sees that there are a variety of failures listed, not only for nonconformances but also complaint handling as well. If one does not investigate properly, one cannot determine the root cause.

For example, if an operator mixes something too long, the cause of the problem is that the operator was mixing too long. But what is the root cause? Why did the operator over mix? Was the operator distracted? Did the operator leave the production site to do something else? One cannot truly prevent this from happening in the future unless the root of the problem is really known. The FDA examines root causes.

Another form of documentation that the FDA looks at is how the water system is validated and routinely tested and how a cleaning validation is performed. Please note that all documentation, especially deviations, need to be justified on the basis of scientific principals, not on the basis of assumption or “I think it’s a good idea.”

Closeout Meeting

After the FDA concludes its inspection, it has a closeout meeting where the Form 483, which is the Notice of Inspectional Observations, is presented. Most of us in the business now consider this a deficiency notice because one never sees compliments on the inspectional observations, only faults or violations of the regulations.

At this time, one can possibly annotate the Form 483 with corrections or possibly even challenge a finding as not being correct. The inspection should end with an amicable conclusion. All inspections should be used as learning experiences.

Note that FDA inspection findings are limited due to the amount of time that the inspector or inspectors have spent at the site, and they always qualify the findings on the Form 483. Also, if no Form 483 is issued, it does not mean that the FDA has approved of everything that is occurring in the facility. It merely indicates that based upon the time and what the inspector examined, the company was in compliance with those items. This is not an invitation to be complacent.

In conclusion, use the FDA inspection as a learning tool and not as something negative or adversarial. It is actually a taxpayer-paid event, which should be used positively.

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