Gotta give the FDA some credit here. In addition to its transparency initiative we’ve talk about before, the agency is also trying to remove some of the mystery about how it handles inspections and other inner workings at the FDA. From where I sit, it appears to be a sincere effort and I believe it is helping outsiders better understand what the FDA is trying to do – and how it is trying to do it.

For example, at the second in a new series of monthly online webinars, FDA’s Michael C. Rogers, deputy director, Office of Regional Operations, said today (March 25, 2010)  tried to outline how an FDA inspection tends to work, and what drives inspectors before, during and after an inspection.

As an aside, Rogers also said that the agency currently has about 1,800 total inspectors across its full portfolio, though food gets the bulk of the bodies. He also said there will be more foreign inspections this year, and that the number should continue to grow.

Inspections are based on risk, Rogers said. In other words, the riskier the potential drug, device or food item, the more likely they will be inspected.

Most inspections are unannounced, Rogers said. Before they go on-site, the inspector on inspection team will look at previous inspection reports and identify what corrective actions were promised during prior inspections. They also prepare inspection tool kits with sampling equipment, info to drive inspection based on guidance documents and the Investigation Operations Manual. They also carry a camera to document evidence.

They also conduct “for cause” inspections driven by consumer complaints or other outside activity.

Typically, the inspection begins with a discussion with management to explain the purpose of the inspection, and they try to learn about the corporate structure and any changes made since last inspection. They also ask about complaints, positive tests or returns. Answers to those questions help FDA inspectors focus their on-site efforts.

Next, they go to the physical manufacturing area. They try to observe and understand the on-site process. They ask about acceptance criteria and want specifics on failures, especially the reasons.

Inspectors also draw a diagram of the facility showing the manufacturing process from start to finish. They’re looking for problems in the system and looking to identify critical control points in the manufacturing process.

FDA inspectors then identify procedures in place and assess if company is actually following them. They also look for controls in place to mitigate any contaminated products.

They also look at training and cleaning programs. They also watch employees while they are actually making the product.

If they find evidence of an adulterated product, they collect evidence based on inspector observations and collect samples to prepare their case for possible legal action in court.

At conclusion of inspection, the FDA team meets again with management. They then inform the top company official what is in the official Form 483. That form documents observations during the inspection but does not include final recommendations. They also ask for the firms corrective actions planned or in place to get into compliance.

These corrective actions are taken into account as agency formulates official recommendations.

After the inspection at the firm, the inspector develops a report back at the home office. It includes evidence collected and what the firm has already agreed to do about any shortcomings.

In some cases firms can offer voluntary corrections. But sometimes the agency decides it needs enforcement action such as a warning letter, and can also impose civil and/or monetary penalties.

The webinar was extremely popular. In fact, it “sold out” so many who tried to join it could not get in to the live event. There will be a recording available on Monday March 29.

UPDATE: Slides are now available from this event here in PDF format.

Ken Miles, a 28 year veteran of the FDA, is today a widely-respected industry consultant to the medical device industry. He draws on his extensive experience to help firms effectively and efficiently comply with FDA requirements. Ken’s expertise includes evaluating Good Manufacture Practice (GMP) and Good Laboratory Practice (GLP) compliance, Quality System Regulations, and QSIT certification inspections (Management, Design, Process Controls, and CAPA).

In this multi-part series, we talked with Ken about FDA medical device inspections, CAPA, quality systems, audits, training and more.

Q: Where do you think companies fall short when it comes to implementing CAPA systems?

A: Some companies have a great CAPA program that is tied in with metrics, management reviews, etc., but ultimately may be only looking at trend analysis studies of post-production products. Unfortunately, they neglect trends with suppliers and internal production operations, or visa versa.  Valuable data can be obtained for correcting problems in their factory by looking at all trends: suppliers’ and in-house non-conforming materials and components, scrap rates, training issues, complaints, competitors’ non conformances (ie Warning Letter), etc.  Sometimes they’ll discover ”a peak in noncomformance with a certain product line”, but they fail to break it down to reveal that the nonconformance(s) only involve one or two models within the product line which is often the real culprit.

Company managers need to ask themselves, is it one model or all models? A certain shift? A certain part of the plant? Finding the root cause is very important in order to effectively resolve the problem(s). Companies need to isolate the problem and find out if it’s widespread, model specific, or a component. The big picture of using metrics is great, however, if you can’t drill down to the specific problem and root cause, then it’s really not solving the problem.

Q: Can you give us some examples of what you saw as an FDA inspector?

A: One time I was at a large global manufacturer and they had a lot of returned motherboards for ultrasound systems (hundreds of boards returned per month.) Instead of analyzing and finding the root cause of the problem of all these returned boards, they would simply rework and repair them – over and over again. These boards had a very high rate of return, but they would all just go into a big hopper for rework. They should’ve taken the time to do a root cause analysis, but they didn’t, preferring to continue to fix them. None of this was logged into a system, and no failure investigations were ever conducted.  Think of the risk to consumers and to the companies’ reputation and earnings! Think of the enormous waste in time and funds and other resources used for fixing the same problems over and over again.

This firm ended up having a major investigation by the FDA with recalls and monetary fines in the millions of dollars. If they had an effective CAPA system in place with root cause and failure investigations, they could’ve fixed the problem once and for all instead of reworking hundreds of motherboards per month.

Q: Why do you think medical device companies have such a problem with CAPA?

A: The biggest problem I see has to do with a lack of human resources. Typically a person in charge of CAPA has too many tasks and things tend to fall through the cracks. This generally happens to smaller companies with growing pains. That said, it also happens with the biggest ones, too. Bottom-line: the failure is about not devoting enough resources to CAPA, and letting other issues distract them because they are overworked.

Click here to learn more about CAPA Systems.

In August, Commissioner of Food and Drugs Margaret A. Hamburg, M.D., outlined her commitment “to prevent harm to the American people” through swift, aggressive, and effective enforcement of FDA laws and regulations at a Food and Drug Law Institute (FDLI) meeting. Last week, FDA officials speaking at the FDLI meeting on enforcement reaffirmed that commitment, warning that “past performance is no measure for future performance” and that companies can expect a “flurry of warning letters.”

FDA staffers have indicated that the agency’s ramped up enforcement efforts will include a holistic and collaborative approach between the agency’s centers in such areas as advertisement enforcement; “blitzes” focused on undeclared allergens, label reviews and warehouse inspections; and data quality.

Among these initiatives, the Center for Drug Evaluation and Research (CDER) has indicated that its approach will include paying closer attention to compliance weaknesses and sloppiness as signs that other reporting could also be sloppy, ensuring proper monitoring of scientific research and data for new drug applications, and working with other centers on matching enforcement priorities.

The Division of Drug Marketing, Advertising and Communications (DDMAC) has also stated that it will dedicate more resources to identifying the most serious violations and getting more actions, through paying closer attention to promotions that could wield the greatest negative impact on public health. DDMAC will also be paying close attention to newly approved products, products with significant risks, or products cited in the past or currently subject to a complaint.

More information on the FDA’s increased enforcement efforts is available at here.

See also: Don’t Ignore 483s…it’s in Your Best Interest to Respond in Writing

See also: The Most Common Drug and Device GMP Items

Mark Mansour is a partner in the firm, Bryan Cave, LLP

FDA Commissioner Margaret A. Hamburg put industry on notice in a brief but well orchestrated rollout of FDA’s new enforcement policy.  The message, in Dr. Hamburg’s own words, is that “the FDA must be vigilant, the FDA must be strategic, the FDA must be quick, and the FDA must be visible.”  On the job now for just shy of three months, Commissioner Hamburg addressed a group of industry representatives, attorneys, consumer representatives, and media at an August 6th event sponsored by the Food and Drug Law Institute in Washington, D.C.

Dr. Hamburg expressed concern about what she described as “unreasonable” delays in FDA enforcement actions in the recent past, and said that “serious violations have gone unaddressed for far too long.”  She observed that that the enforcement process is “too long and arduous when the public’s health is in jeopardy.”

Hamburg laid out a series of steps FDA intends to take, presumably starting immediately:

• Set post-inspection deadlines. The FDA will establish a clear timeline for regulated industry to respond to significant FDA inspection findings, generally giving no more than 15 days to respond to such findings before the agency issues a warning letter or takes other enforcement action.
• Take responsible steps to speed the warning letter process. The FDA will streamline the warning letter process by limiting review of warning letters by the Office of Chief Counsel to those that present significant legal issues.
• Work more closely with FDA’s regulatory partners. In some cases, such as with food safety issues, state, local, and international officials can act more quickly than the FDA. When public health is at risk, the agency will coordinate with its regulatory partners to take rapid action.
• Prioritize follow-up on warning letters and other enforcement actions. The FDA will work quickly to assess and follow up on corrective action taken by industry after a warning letter is issued or major product recall occurs.
• Be prepared to take immediate action in response to public health risks. To better protect the public health, the agency is prepared to act more quickly and aggressively to deal with significant public health concerns and violations. Such actions may occur before a formal warning letter is issued.

Develop and implement a formal warning letter “close-out” process.  If the agency can determine that a firm has fully corrected violations raised in a warning letter the agency will issue an official “close-out” notice and post this information on the FDA Web site. This will be an important motivator for corrective action by manufacturers.

What Hamburg did not address is what will be done to streamline the approval process for medical devices and for other FDA-regulated products, nor did she address the persistent and growing problem of unqualified inspectors roaming plants armed with the authority to enforce.  No one disputes the need for vigorous, predictable enforcement, but FDA’s credibility is not threatened solely by the perception that it cannot keep the marketplace safe.  It is threatened as much by the reality that for those products that require pre-market approval, there is no end in sight to the delays and the absence of sufficient qualified technical staff to evaluate products and therapies and facilitate their release to the medical and patient community.  Ignoring that problem while focusing on regulating to the worst common denominator of the industry, by any a measure a very small minority, may make great headlines. Unfortunately, it leaves unaddressed some of FDA’s major deficiencies.

Mark Mansour is a partner in the firm, Bryan Cave, LLP

Even though there’s no regulatory requirement to respond to an FDA 483 inspectional observations report, it’s in your best interest to do so in writing, according to FDA sources. In a recent presentation by Anita Richardson, Associate Director for Policy Office of Compliance & Biologics Quality, she outlined four reasons for submitting a comprehensive 483 response, and eight suggestions for an effective response.

Four reasons for submitting a well-prepared and timely 483 response:

1. Could possibly mitigate an FDA compliance decision for further action (warning letter, etc.) “As a general rule, a Warning Letter should not be issued if the agency concludes that a firm’s corrective actions are adequate and that the violations that would have supported the letter have been corrected.”
2. Demonstrates to the FDA (and other stakeholders) an understanding and acknowledgement of the observations
3. Demonstrates to the FDA (and other stakeholders) a commitment to correct, i.e. the intent to voluntarily comply
4. Establishes credibility with FDA

Eight suggestions for an effective 483 response

1. Include a commitment/statement from senior leadership
2. Address each observation separately
3. Note whether you agree or disagree with the observation
4. Provide corrective action accomplished and/or planned; tell FDA the plan
   • Be specific (e.g. observation-by-observation)
   • Be complete
   • Be realistic
   • Be able to deliver what you promise
   • Address affected products
5. Provide time frames for correction
6. Provide method of verification and/or monitoring for corrections
7. Consider submitting documentation of corrections where reasonable & feasible
8. BE TIMELY

Good advice. And remember…

“A well-reasoned, complete, and timely 483 response is in your best interest.”