It got lost in the mail” is an age-old excuse that some people use to deal with bills and other bad news that arrives in their mailbox. But, if the envelope is from the U.S. Food and Drug Administration, it’s not a good idea to play dumb or act indifferent.

No medical device manufacturer wants to get a Form 483 or a Warning Letter from the FDA. However, if it does happen, manufacturers must take every possible step to address the issue.

While FDA Form 483 has been around for decades, there’s been an increasing amount of incidents in recent years. And, 483s and Warning Letters are becoming increasingly rigorous and complex.

The form notifies a company’s management of “objectionable conditions” at the conclusion of a routine inspection of a production facility. It is presented and discussed with the company’s senior management. Companies are encouraged to respond to Form 483 in writing with a corrective action plan and then implement that corrective action plan expeditiously.

According to the FDA, a Form 483 is issued “when an investigator has observed any conditions that in their judgment may constitute violations of the Food, Drug and Cosmetic Act and related Acts. Observations are made when, in the investigator’s judgment, conditions or practices observed would indicate that any [medical device] has been adulterated or is being prepared, packed or held under conditions whereby it may become adulterated or rendered injurious to health.”

FDA investigators are instructed to note only what they saw during the course of their inspection. Companies are responsible to “take corrective action to address the cited objectionable conditions and any related non-cited objectionable conditions that might exist.”

According to the Emergo Group, a medical device consulting firm, FDA quality system inspectors have issued Warning Letters to manufacturers at an increasing rate since 2005. And, the steady increase in Form 483 observations and Warning Letter citations coincides with higher rates of FDA Quality System Regulations compliance inspections since 2008. For instance, FDA officials conducted 1,423 quality system inspections at medical device manufacturers in 2008 vs. 2,121 inspections in 2011 and 2,087 in 2012.

“More firms are getting challenged today,” says Larry Stevens, a senior consultant at The FDA Group LLC. “Over the last few years, the FDA has become more enforcement-minded and tougher on medical device manufacturers, due to the change from the Bush administration to the Obama administration. The agency received a major budget increase and doubled the number of people in its field force in 2008.

“Some of those people are doing really tough inspections that weren’t seen 10 years ago,” adds Stevens, who previously worked for the FDA for 22 years and spent 18 years as a regulatory affairs and quality assurance executive in the medical device industry. “As a result, medical devices manufacturers that think they’re doing OK can end up with an inspection that results in a long Form 483.

“That’s a major concern for them, because senior management often views a Form 483 as an indictment of their quality systems,” Stevens points out. “It creates a lot of internal angst and places tremendous pressure on the people in charge of quality.”

Another reason the FDA has stepped up inspections of manufacturers is the meningitis outbreak of 2012. In September 2012, 751 people nationwide contracted fungal meningitis after receiving injections of a contaminated steroid. Sixty-four people died.

According to Stevens, companies that produce high-risk devices are typically targeted by FDA inspectors. Products in that category include Class III devices, such as blood pumps, heart stents, infusion pumps and orthopedic implants.

“Recent advancements in electronics and software have created an environment in which there’s a lot more things that can potentially go wrong with medical devices,” explains Stevens. “Whenever a glitch occurs with a product or a company issues a recall, the FDA goes after them.”

No Laughing Matter

A Form 483 is not something that can be put in a file and forgotten about. It always needs to be taken seriously.

However, 483s can vary from company to company and from one FDA inspector to the next. The blank form itself is standard, but it can range in length from one page with four observations to 50 pages with 100 observations.

“It depends on how long the investigator stays in a plant, which can vary from one day to several weeks,” says Stevens. “A typical length is two pages and 12 observations.”

No matter how long or how detailed it is, a Form 483 is often stressful to medical device engineers.

“No one enjoys getting feedback that’s critical of their process,” says David Ball, president of Ball Consulting Group LLC. “And, when it’s a government official who comes into your plant and does that, it can be intimidating.

“In addition, there’s never really any closure,” notes Ball. “The FDA may come back with additional observations or a different action. Or, they may be satisfied and do nothing. Either way, no one ever says ‘everything’s fine now and we’re settling the case,’ which can be unnerving.”

“It is very typical for a device manufacturer to have several observations that require attention,” says Leslie Tector, a partner and member of the health law practice group at Quarles & Brady LLP. “The observations can range widely, and the FDA provides recent trends on its Web site.

“Institutions that fail to adequately address the observations, or which have significant violations, are at increased risk for more severe penalties being issued, including issuance of a Warning Letter, seizure of product and issuance of an injunction preventing sale of products,” warns Tector. “In the most serious instances, criminal prosecution is a possibility.”

“The real problem is when a company incurs several 483s and the FDA decides to issue a Warning Letter,” adds Jack Slovick, president of Methodize Inc., a medical device consulting firm. “The Warning Letter is concerning and really puts the company on FDA’s radar.

“I have seen companies that are issued 483s at a particular inspection, and then either ignore them or take too long to address them,” says Slovick. “A Warning Letter is then issued and if the Warning Letter is not taken seriously, then consent decree, FDA remediation or injunctions quickly follow suit. When a company gets this far into this process, it has really upset the FDA.”

A Form 483 can be intimidating for several reasons. “First, it represents the findings of an FDA investigator after spending time going through a company’s processes and quality system records,” explains Tector. “Unlike internal audits, vendor audits or even ISO audits, FDA inspections are conducted for law enforcement purposes.

“The observations found by the FDA investigator can, and many times do, lead to further agency action against a company,” warns Tector. “The last thing that any company wants is for the 483 to escalate into a Warning Letter.”

A 483 can also be intimidating because of the way in which it is written. “FDA uses canned observations known as Turbo 483 observations,” says Tector. “The way in which the observations are written oftentimes make the inspectional observation out to be much more significant than the situation truly is.

“For example, we have seen several instances where a company’s Standard Operating Procedure (SOP) is missing a provision, or may not sufficiently address a requirement in the Quality System Regulation (QSR),” Tector points out. “However, the 483 will more broadly state that the company either does not have a procedure in place, or that the SOPs are inadequate.

“For deficiencies in a Medical Device Reporting SOP, the FDA Turbo citation is: Written medical device reporting (MDR) procedures have not been [developed] [maintained] [implemented],” says Tector. “Whichever version is used by the investigator tends to make the omission of a regulatory requirement in an otherwise compliant SOP seem more onerous than what was actually observed.”

According to Tector, a 483 can also seem daunting when an investigator hones in one set of facts or situation and cites the company for the same issue in each quality subsystem.

“For example, if a complaint is received pertaining to a device that does not meet specification, the 483 could cite the company for: inadequate production processes; inadequate processes governing final inspection and release; inadequate training; inadequate management controls (by virtue of the issue occurring in the first place); or inadequate internal audits, among others,” says Tector. “This same set of facts also could lead to observations regarding corrective action and preventive actions (CAPA), complaint investigations and MDRs, depending on the circumstances.”

Best Way to Respond

The most effective way to respond to a Form 483 is in writing and within 15 days of issuance.

“When a corrective or preventive action cannot be completed within the 15 working days following issuance of the 483, provide the date by which the action will be completed,” suggests Michael Heyl, a partner at Hogan Lovells LLP who specializes in medical devices. “The response also should commit to follow up with the agency by providing the evidence of implementation upon completion.

“There are several schools of thought regarding how to respond to a 483,” adds Heyl, whose expertise is in post-market enforcement matters. “We have had great success using the following formula:

“First, each inspectional observation should be responded to in a narrative format,” Heyl points out. “The response should tell the entire story surrounding the observation and the company’s processes that are the subject of the observation. The sole purpose here is to provide the reader of the response with as much information as possible.”

The person reading the response and making the Warning Letter decision is not the investigator who was on site. It is typically a compliance officer or a person in the FDA’s Compliance Office or Center for Devices and Radiological Health.

“Regarding the responses to the individual 483 inspectional observations, to the extent applicable, the response should provide as much advocacy as possible to defend how the company handled the specific files or issues referenced in the 483,” claims Heyl. “For example, if the company performed certain activities, but just did not document them sufficiently, it is important to note this.

“Also, it is important to identify the company’s SOP that was in place at the time of the inspection,” adds Heyl. “Remember, the manner in which the Turbo 483 citation is crafted may make it appear that no SOP was in place at all.”

The 483 also should identify what the company did to investigate the issue and identify all of the corrective and preventive actions being taken to address the inspectional observation.

 “When identifying corrective and preventive actions, if those actions have been completed within the 15 working days, evidence of implementation should be attached to the response itself,” says Heyl. “For example, if SOPs have been revised, the modified SOP should be provided as evidence of implementation. We have seen numerous Warning Letters issued because a 483 response did not provide evidence of implementation of the identified corrective action.”