10 Takeaways From FDA's 2013 Warning and Untitled Letters: 10 - 6

| 17 June 2013

Here at Regulatory Focus, we read a lot of the Warning Letters and Untitled Letters issued by the US Food and Drug Administration (FDA). In fact, we try to read every single one of them related to pharmaceuticals, medical devices, biologics or dietary supplements.

Why? Because they're often the best way to get a sense of what the agency cares about and where it may be preparing to shift its resources. Several times during the first half of this year, Focus has identified Warning Letter that have preceded crackdowns on companies for similar violations.

We recently went through all Warning Letters and Untitled Letter issued since 1 January 2013 with one question in mind: What should regulatory professionals take away from these letters?

We're pleased to present a list of 10 takeaways from what we think are the most interesting and most important letters sent by FDA this year (so far). (Check out Part 2 of this piece here.)

10.) An Elephant Never Forgets, and Neither Does FDA

An inspection by FDA can be an incredibly stressful experience, even for companies that are well prepared. For those that aren't, the issuance of a Warning Letter is an opportunity to assess weaknesses, formulate improvements and make promises to regulators regarding future plans to improve.

But if a company thinks that FDA isn't going to remember these promises, a February 2013 letter to Korea's Sometech Incorporated - a medical device manufacturer - is a good indication that this is a losing proposition for companies to gamble on.

FDA's letter goes on to explain that in addition to current deficiencies, the company had failed to correct 10 specific deficiencies noted in a 2010 Form FDA-483 sent to the company. "Corrective and preventive Actions were not completed for these observations," FDA noted. "Changes were made to your firm's procedures," FDA said, "But there was no evidence of implementation. Deficiencies in files and records for these observations were not corrected." [Read More…]

The Takeaway: Follow through on any promises made to regulators, especially in the context of a deficiency in an FDA-483.  Otherwise, expect to find your company subject to an import alert, as Sometech now is.

9.) Keeping Things Clean

How do you maintain sanitary conditions when you are unable to wash a piece of equipment? No, that's not a hypothetical - it's a question asked of Keystone Laboratories in March 2013 by FDA after the agency found that the company was using "wooden sticks" and cardboard covers on its production equipment. The letter went on to note that both came into direct contact with the drug products, and that neither were appropriate for use in the manufacturing environment because they could not be properly sanitized.

"These materials (wood and cardboard) are not appropriate for drug manufacturing.  Their construction makes them difficult or impossible to clean and can therefore become a source of microbial contaminants, dirt, and residues of other drugs that may alter your product's quality," FDA wrote. [Read More…]

The Takeaway: Pay attention to FDA's regulations under 21 CFR 211.63, which require that equipment needs to be of appropriate design, size and location for its intended use and to facilitate cleaning and maintenance.

8.) Entomophobic Investigators

It's a perennial problem, but it bears repeating: The only living things in your facilities should be your employees or the biological products you intend to produce. And while microbial contamination is nearly impossible to eradicate, the same can't be said for larger organisms like bugs.

Several times already in 2012, FDA has called out manufacturers for the presence of insects in their respective facilities. An FDA-483 released to the public in June 2013 to compounding pharmacy Main Street Pharmacy cited spiders in the company's clean rooms; a Warning Letter in June 2013 cited a larger, pervasive "insect issue" that had gone unresolved; and an April 2013 Warning Letter to a Japanese manufacturer found hundreds of insects stuck to insect catchers located in close proximity to manufacturing equipment.

It's not that inspectors are entomophobic (fear of insects) - we think - but it does reflect a desire to cut down on potential sources of contamination and adulteration.

The Takeaway: Sure, it's not a bird, which was found at another compounding pharmacy last year, but if there's a takeaway to be had here, it's to be mindful of pest remediation requirements under 21 CFR 110.35(c), 21 CFR 820.150, and 21 CFR 211.56.

7.) No-Ply Toilet Paper

One of our favorite Warning Letters this year referenced something that most regulatory professionals probably don't give much thought to during pre-inspection checklists: Is there toilet paper in the bathroom?

The May 2013 Warning Letter to Desert Rose Manufacturing cited regulations under 21 CFR 111.15, which required facilities to maintain certain basic sanitary controls for their facilities. In the case of Desert Rose Manufacturing, its violations were of 21 CFR 111.15(h), which mandates that a company "must provide its employees with adequate, readily accessible bathrooms…kept clean and must not be a potential source of contamination to components, dietary supplements or contact surfaces."

Inspectors said the company "failed to keep paper towels and/or toilet tissue in the production area and the men's toilet in the production area did not flush." More than just a reason to gripe, FDA noted that the problem could potentially lead to the production area for the supplements becoming contaminated if staff were unable to properly clean their hands. [Read More…]

The Takeaway: Your manufacturing line isn't the only piece of equipment you need to be mindful of. Make sure the porcelain in the restroom is functioning properly, and that you have enough toilet paper for your employees to use. Who knows -- two-ply tissue might even help employee morale.

6.) Fair and Balanced

FDA's advertising regulations are notoriously tricky, as its Untitled Letters illustrate on a monthly basis. Among the most difficult areas of compliance in 2013 continues to be the concept of "fair balance" - the requirement that all advertisements give equal treatment in all respects to both the safety and efficacy of a product while making sure that all relevant aspects of both are included.

2013 has already seen several companies run afoul of this requirement. For example, an Untitled Letter sent in February to ParaPRO chided the company for omitting "all risk information" in the ad, falling afoul of FDA regulations. "By omitting the most serious and frequently occurring risks associated with the drug, the VNR misleadingly suggests that Natroba is safer than has been demonstrated," FDA concluded.  [Read More…]

An Untitled Letter sent in April to Israeli generic pharmaceuticals giant Teva focused more on the aesthetic choices made by the company in an advertisement. The company had chosen to present points about the efficacy of its product using prominent text, colorful photos, graphics and lots of whitespace to make it easy to read. In contrast, risk information was crammed together, had no headers to distinguish sections, was in black and white, and was otherwise difficult to read. "The overall effect of this presentation undermines the communication of important risk information, minimizes the risks associated with clozapine, and misleadingly suggests that clozapine is safer than has been demonstrated," FDA wrote. [Read More…]

Finally, a June 2013 Untitled Letter sent to Sigma tau Pharmaceuticals leveled claims similar to those made in the Teva letter, with favorable efficacy data presented using large bolded headlines and colorful graphics in the first seven pages of a ten-page pamphlet, with safety data relegated to the back on the pamphlet and using no graphics and a size-10 font size. [Read More…]

The Takeaway: Fair balance extends to a huge number of factors, including text color, text size, the use of headers, the location of risks within a multi-page advertisement, graphics, photos and other means of accentuating information. Make sure that advertisements pass FDA scrutiny by comparing how various bits of information are presented in relation to one another.

Check out Part 2 of this piece here.


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