As FDA inspection guidelines and expectations undergo significant evolution, Ron Ball explains how to prepare for all eventualities.

Over the last 3-4 years the FDA has been targeting its inspectional resources to establish the infrastructure needed to inspect the growing number of foreign drug manufacturing facilities who now ship products to the US. The agency is now waking up to the fact that it has fallen far behind schedule in inspecting drug manufacturing sites in the US, and is just now beginning to re-focus its attention on the backlog of audits at US drug manufacturers. Many US medical gas firms have not seen an FDA inspector in their facility for years, but that is about to change.

This article will examine some do’s and don’ts when preparing for your next FDA inspection.

There is a new breed of inspector
Traditionally, medical gas sites have often served as the training ground for new FDA inspectors. This is probably truer for cylinder filling sites than for air separation units (ASUs).

Routinely we have seen experienced FDA inspectors showing up at medical gas sites with 1-3 trainees in tow. A large number of other medical gas sites have had the experience of being visited by an FDA inspector who was clearly very junior and still learning his/her craft. This long-standing trend appears to be changing. In the last 12 months we have begun to see highly experienced FDA inspectors visiting medical gas sites.

The same group of inspectors is beginning to show up at different medical gas companies in the same geographic area, giving the appearance that the FDA is now focusing on using the same group of inspectors to concentrate on the medical gas sites in a designated geographic area. As this trend begins to spread nationwide, this will result in the majority of medical gas firms being visited by a vastly more experienced FDA inspector than they might have historically seen in the past.

It also appears that the FDA has spent time training this new group of inspectors. Many of them now appear to be significantly more knowledgeable about the gases industry and the FDA compliance requirements applicable to our industry than what we have seen in the past.

A new inspectional process
The duration of medical gas inspections has always been highly variable, ranging from weeks to a few hours. Welding and gases distributors and homecare firms routinely experienced FDA inspections that lasted less than a full day from beginning to end.

During these abbreviated inspections it was typical for the FDA inspector to show up mid morning, look at a handful of records, conduct a closing conference, and leave by mid afternoon. Usually, no 483 citation was issued unless there were glaring deficiencies.

Based on recent inspections, the approach to medical gas audits appears to be changing. The last dozen or so FDA audits we have been involved with have all been conducted using what appears to be a common agenda. This agenda appears to be drawn directly from the requirements in the FDA’s 2003 Medical Gas Guidance Document. While that guidance document is still in draft form, that does not appear to be stopping FDA inspectors from using it as their guide to conducting audits at medical gas facilities. As a consequence the 2012 FDA inspections at medical gas sites appear to be much more comprehensive and are taking longer to complete.

Getting prepared
The core of any FDA compliance program is the procedures you use to fill, test, warehouse, and distribute your products. If your procedure manual was written 10 years ago and there has been very little, if any, effort invested in keeping it updated, it is a safe bet there is some work needed in this area.

The FDA expects that procedure manuals will contain the specific steps needed to actually accomplish a task, and shall be written in sufficient detail to explain the task to the line employees. All too often we see procedures where the firm has simply copied the language from 21 CFR, section 210, into their procedure manual. That kind of approach is no longer sufficient. The FDA expects to see clear and concise procedures that provide adequate guidance on how tasks are to be conducted.

Recent FDA audits have taken a very close look at how the firm’s QC Unit is organized, what QC Unit procedures are in place for executing QC tasks, as well as reviewing whether the responsibilities and authority of the QC Unit have been clearly defined in the firm’s operating procedures. Recent inspections have taken a very close look at the degree of independence of the quality unit at medical gas firms. If your procedures do not unequivocally delineate these specific QC Unit requirements, this is an area where you can expect the FDA’s focus to fall.

The FDA is also looking to see if firms have an emergency plan for natural disasters; do you have procedures for change management, vendor audits, and do they have procedures for reporting a Med Watch event? The first step in evaluating your medical gas procedures would be to conduct a gap assessment against the 2003 Medical Gas Guidance Document.

Current FDA inspections are closely reviewing training records and personnel qualification files. The FDA expects to see employee training conducted against a matrix by job classification or description. If your medical gas employees have not received documented training in the last 12 months, expect to be cited for that. In addition to training records, the FDA will expect to see training agendas and training materials on file as well.

Some FDA inspectors are also asking if a firm has conducted testing of employees after the training to establish competency to verify if the training was adequate - and if so they are reviewing the test results. The agency now expects employees to have attended a focused FDA training session, not just a safety or management/team meeting with a few FDA related topics on the agenda.

If you are doing your own FDA compliance training in-house, the FDA will expect to see that at some point your internal trainer did receive training from an outside source. Since almost every medical gas firm uses operations personnel to populate their QC Unit, the FDA will also expect to see in place a focused QC Unit training and qualification program for those members of the QC Unit - again, with an agenda and materials.

Finally, if you have modified or updated procedures, then the FDA will expect to see where remedial or update training has been provided to all affected employees. This re-training expectation extends to even the most minor change or update to your procedures.

Follow your procedures
A time honored FDA inspection method is for the inspector to read and digest your written procedure and then observe your employees actually conducting the tasks covered by the procedures. The FDA knows it is not uncommon for employees to have developed short cuts on the floor or incorporated bad habits into their tasks. In 2012 you can expect to receive a citation for any instance where your procedures do not match how your employees conduct the task, even if all they are doing is conducting the right steps in the wrong sequence. Not only will the inspector cite you for not following your own procedures, it is also likely they will cite you for inadequate training. The justification for this is that properly trained employees would understand completely the requirements in their procedures and should be following them.

The most effective method of preparing for this type of audit technique is to conduct task observations of your employees performing their medical gas tasks. Not following your own procedures is one of the top 10 most frequently cited FDA violations, so expect the FDA to look closely at this part of your compliance program.

Record keeping is king
The difference between medical gases and industrial gases has nothing to do with purity or strength of the gas and everything to do with the trail of documents that follows medical gases from the bulk plant source to the end-user.

As far as the FDA is concerned, without an adequate and complete paperwork pedigree, medical gases are considered adulterated. For this reason diligence in documenting each and every step in the manufacturing and distribution process is an essential skill for a well-run compliance program. It is also another area that the FDA can be expected to look at closely during your next audit.

Common errors leading to citations include improper corrections to documents, missing data, missing signatures or initials, and tasks documented after the fact. The FDA is looking closely to see if medical products are kept in quarantine until they are released by the QC Unit. A number of firms filling micro bulk units and medical vans have recently been found to be in violation of these requirements. The van/micro bulk unit must be analyzed and the paperwork approved for release before the unit is moved out of quarantine. From a practical standpoint this means that you cannot fill and release a van/micro bulk unit without two trained employees on-site; one person who conducts the filling and analysis of the unit, and the second person who acts as QC Unit reviewer.

Expect the FDA to review your fill records. In a couple of instances the inspector asked for a full year of records. If that is the case, depending on the volume of medical gases at your site, you can expect the FDA auditor to be there for a while reviewing all that paperwork. Usually, once the inspector sees the amount of documents that kind of request entails, they often tone down their request.

Also expect the FDA to look closely at calibration records, especially the certifications of the calibration gases you use to calibrate your analyzers. If you cannot produce a certificate of analysis for your calibration gases that states they are traceable to NIST (National Institute of Standards & Technology), then expect to be cited. Firms that fill and analyze a cylinder and then use the gas from that cylinder to calibrate the same analyzer will probably find themselves receiving multiple citations.

But we are now seeing the FDA asking questions about the record-keeping of maintenance activities for fill manifolds, pumps, and more. The same holds true for change management. The FDA is asking to review the records firms keep of modifications/changes/upgrades to their equipment and systems. These are all record-keeping issues that most FDA medical gas inspections have never really focused on before. However, they illustrate the expanded focus that the FDA is employing in the latest wave of site audits in our industry.

Audit yourself
An internal or third party audit is the most effective means to find and fix any gaps in your compliance program before the FDA shows up at your door.

Unfortunately, the problem for many small firms is that the same person who wrote the FDA compliance program, and who is responsible for employee training is also the same person who gets tapped to conduct an internal audit. It can be really hard to be as objective as needed in these kinds of situations. For this reason firms often rely on outside resources to conduct site audits, so they can get a more objective look at their FDA compliance program.

The B&R mock FDA audit program looks at your facility as a typical FDA inspector would. We know what kinds of questions they are asking, and what documents they expect to see. We also conduct task observations of your employees to gauge their compliance with your procedure requirements. Companies all over the industry have us do an audit every year as a report card on their FDA program - and to keep them ready for the next FDA inspection.

An ounce of prevention
Receiving a visit from the FDA is always a stressful event, no matter how prepared you might be. Spending time and effort in preparing for your next inspection will help ensure that the event goes as smoothly as possible, and can help eliminate a lot of the stress associated with this kind of event.

Tapping into a professional resource will help make that preparation work as effective as it can be. B&R offers a number of programs and services designed to help firms prepare for and survive their next FDA audit.If you have questions about FDA audits or any FDA medical gas compliance issue, please give us a call.

More Information
If you are not willing to have a third party audit your facility, then you should at least try to develop an audit checklist to guide the process. One resource in developing that checklist is the guidance that the FDA provides agency inspectors contained in the FDA inspector manual. Section CPG Spec. 435.100 covers Compressed Medical gases and outlines specific instances where the inspector can and should issue a warning letter. This information can be found at:
While this was last updated in 1992, it still is a valid document that can be used as a starting point to develop your own audit checklist.

Ron Ball
For more information on regulations that affect medical gas producers
and end-users contact: Ron Ball at B&R Compliance Associates LLC
+1 (317) 297-8518; e-mail:;
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