FDA is quickly demonstrating a more aggressive enforcement posture toward drug manufacturers under President Obama.

Drug GMP enforcement activity surged in the second quarter, judging from factors such as issuance of warning letters. FDA issued 14 drug GMP warning letters from April through June - up from just four during the first three months of 2009.

Already, with 18 drug GMP warning letters in the first half of calendar 2009, FDA has doubled the annual warning letter rate of the previous four fiscal years. And if the blistering pace seen in the second quarter continues, the annual rate would soon reach levels not seen since the Clinton administration.

There were also a few cases where the agency took enforcement actions with little or no warning. Rather than formulating warning letters, in some cases the agency has simply redacted Form 483 inspectional observation reports and other enforcement documents and pushed them online, while proceeding with seizures and injunctions.

Just two months into her tenure as FDA commissioner, Margaret Hamburg Aug. 6 announced six enforcement initiatives that could further increase the rates of GMP warning letters, seizures and injunctions.

Stronger enforcement not only helps consumers, it helps industry too "by maintaining a level playing field for safe products," she said. "Making sure that offenders are held legally accountable prevents companies from having to choose between doing the right thing and staying competitive."

Meanwhile, over the past two months, FDA noted a flurry of drug recalls, including a massive Class II recall at Advantage Dose in Shreveport, La., that began last Thanksgiving eve.

The Need for Speed

Hamburg emphasized the need for speed in her remarks to the Food Drug Law Institute in Washington.

The six initiatives she announced all were focused on expediting the enforcement process:

A 15-day limit for responding to Form 483 reports of inspectional findings would end delays associated with belated and multiple responses, which in the past FDA has felt obliged to answer in its warning letters.
A decision to have FDA's Office of Chief Counsel review only those warning letters that involve "significant legal issues" would speed issuance of routine warning letters.
A pledge to work more closely with state, local and international regulators would enable quicker action.
A priority placed on warning letter and recall follow-up would ensure quicker resolution of corrective actions.
A willingness to act without warning against public health risks would short-circuit all warning letter-related delays.
And plans for a new warning letter closeout process that culminates in a public closeout notice would give manufacturers extra incentive to put their problems behind them.

Although enforcement metrics such as violations cited and warning letters issued are on the increase, Hamburg stressed that "this isn't about numbers. It's about impact and it's about responding to an issue that has implications for health and safety, in the most timely and appropriate way."

Hamburg stressed that what she does not want "is something that frankly I can see in some past responses, where there's just a lot of back and forth and stall and delay and let's wait and see what the company does."

She is aiming for a "standard of practice" in which the agency is "as transparent as possible about our expectations" and industry "commits to working in as responsive a way as possible to address our concerns."

This will involve laying out timeframes for action "that will help move issues more swiftly toward appropriate conclusions," she said.

Hamburg came back to the point when responding to a question about ambiguities in the Food Drug and Cosmetic Act that FDA has never clarified through regulation. After commiserating about the complexity and opaqueness of food and drug law, she stressed the importance of "trying to get things out in a more timely way."

"I've discovered that the expected time frame for certain things, things that are just routinely accepted, sort of boggle the mind of someone coming from the outside," she said. "Perhaps my own naiveté may help move the ball forward a little bit because some of these time frames just don't seem acceptable to me."

Clock to Start Ticking on Form 483 Responses

The first initiative Hamburg outlined, the program establishing post-inspection deadlines, was further described in an Aug. 11 Federal Register notice.

Beginning Sept. 15, FDA "ordinarily" will give companies only 15 working days to deliver their responses to its Form 483 inspectional observations.

The agency said it would not consider late responses when crafting warning letters, though it would look into them afterward.

FDA plans to try the new approach for 18 months, after which it may continue with it, adjust it or cancel it.

The program would reduce enforcement delays that can result when companies issue delayed or multiple responses, sometimes over many months, describing their various and often ongoing corrective actions. Reviewing and addressing late responses can delay issuance of warming letters.

Chief Counsel Reviews Will be Limited

The second initiative would partly reverse a policy the agency instituted in 2003 subjecting all warning letters to review by FDA's Office of Chief Counsel.

A sharp decline in drug GMP and other warning letters occurred soon afterward, and there was criticism from some quarters that the additional level of review was suppressing enforcement activity (Also see "Drug GMP Warning Letters, Enforcement Could Rebound in Obama's FDA" - Pink Sheet, 1 April, 2009., p. 1).

There were elements within FDA that chafed at the reviews, particularly within the field organization, which had free rein to fire off warning letters at will in the 1990s.

Hamburg told the FDLI meeting that she approved a policy "brought forward" by the acting chief counsel, Michael Landa, "to limit warning letter review to significant legal issues. As a result, most enforcement letters will be able to move forward through a more streamlined process," she said. "This approach is consistent with the FDA's longstanding historical practice."

Assistant Commissioner for Policy David Horowitz later clarified for reporters that under the new policy, the chief counsel's office would only "ordinarily" review letters dealing with a new statute or regulation that the agency has little experience in interpreting, with ongoing litigation, or with a new interpretation or application of a law.

Former Chief Counsel Stresses Value of Reviews

Gerald Masoudi, the last chief counsel to serve under Bush and now a partner with Covington & Burling, takes a different view.

All warning letters merit legal review, he told "The Gold Sheet" because they are "inherently legal documents" that can lead to class action lawsuits and damage companies' reputations.

"As a matter of good government, an agency shouldn't make a statement that somebody violated the law unless an attorney reviewed the statement," he said.

By giving manufacturers a chance to correct problems before the government takes legal action, warning letters imply that such action is warranted. But Masoudi noted that in a case where the chief counsel's office believes an issued warning letter falls short in establishing the case for legal action, it might decline to ask the Justice Dept. to prosecute. This could be embarrassing for the agency - and could undermine its effectiveness.

Limiting legal review to warning letters that pose "significant legal issues" could be difficult because legal review is required first to determine which letters pose such issues, Masoudi suggested.

He acknowledged, however, that it might be possible for agency lawyers to create templates for standard warning letter issues in areas of settled law.

Asked how companies should respond to the new policy, Masoudi encourages them to monitor the quality of warning letters emanating from the agency. Recipients of poor quality warning letters that would have benefited from legal review might want to engage the agency, for example by requesting a meeting to express their concerns, he suggested.

Working With Other Regulators

Regarding the third initiative, working with other regulators, Hamburg noted that FDA already works closely with state and local agencies, and would like to build its working relationships with counterparts in other countries.

"We live in an increasingly globalized world," she said, "and the importance of working with sister regulatory agencies around the globe is increasingly important and a very high priority for me."

She noted that "I actually very early in my tenure as FDA commissioner went over to meet with counterparts in the European Union to talk about how we could work more closely together, how we could work toward increasingly harmonized standards and approaches, and how we could share information, confidentially of course, but to enhance the work of our mutual agencies."

This is an area where progress has been slow, in part because of differences, particularly with European authorities, over whether the U.S. should agree to be bound by the conclusions of other inspection agencies.

FDA also still is waiting for the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme, or PIC/S, to approve its application for membership. It has been taking PIC/S far longer than many in the U.S. would think necessary to decide if the agency warrants inclusion in the group, which functions much like an association of national pharmaceutical inspection agencies.

Officials familiar with the PIC/S process have said one issue is that that FDA authorizes the marketing of drugs but does not license them as it does biologics and devices. The licensing approach is standard in PIC/S.

Swift Follow-up and Closeout Anticipated

Under the new approach Hamburg outlined, FDA will bring enforcement cases to swifter conclusions.

"After a warning letter is issued or a major product recall occurs, we will make it a priority to follow up promptly with appropriate action such as an inspection or an investigation to assess whether or not a company has made required changes in its practices," she said.

Also, she asserted that the agency "will no longer issue multiple warning letters to noncompliant firms before taking enforcement action."

And if FDA determines that it must move quickly against "significant health concerns or egregious violations," Hamburg said, "we will consider immediate action - even before we have issued a formal warning letter."

However, amid all the sticks, Hamburg is offering a carrot to encourage manufacturers to respond to future enforcement actions with prompt corrective actions.

"At my direction, the FDA is developing a formal warning letter 'close-out' process," she said. "If the FDA can determine, usually based on a re-inspection, that a firm has fully corrected the violations raised in a warning letter, we will provide the firm a 'closeout' letter indicating that the issues in the warning letter have been successfully addressed."

The agency would then post public notices of the closeout letters on its website. She noted that not all warning letters would be eligible for the closeout letters. However, she said, "for ongoing violations it could play an important motivating role in spurring corrective action."

Hamburg's Enforcement Agenda

Hamburg went on to give a sneak preview of her agenda for FDA's enforcement program.

She wants to see better integration between the agency's centers and its field organization.

She wants input from public and other stakeholder groups on where to most effectively focus enforcement efforts, while she wants to hear from industry "about where our enforcement efforts do not yield improvements for public health."

She wants to work with national and international partners to secure the industry's increasingly complex global supply chains.

And she wants Congress to provide more effective enforcement tools as the House did the week before when it passed food safety legislation that would give the agency mandatory recall authority for tainted foods.

FDA Already Acting With Little or No Warning

Hamburg's FDA already has shown a propensity for acting with little or no warning in cases of potentially imminent public health risks.

Last year, FDA showed it was willing to take enforcement action, though perhaps not champing at the bit like it is this year.

For example, the Justice Department filed a complaint against Actavis on FDA's behalf last Nov. 13, some three and a half months after the company recalled all products and suspended manufacturing operations at its New Jersey facilities. The recalls had begun in April with overlarge dioxin tablets after FDA investigators had found numerous gGMP violations over a three-year period.

Similarly, a March 2 consent decree with KV Pharmaceuticals, St. Louis, came after five years of annual inspections, each of which generated pages of inspectional observations.

Caraco's Digoxin Troubles

The first harbinger of the new approach came June 25 when, at FDA's request, U.S. Marshals seized drug products manufactured by Detroit-based Caraco Pharmaceuticals Laboratories Ltd.

The seizure was precipitated by an inspection that FDA had completed just the month before in follow-up to an October 2008 warning letter.

The March 11 to May 12 inspection, which FDA said in its seizure press release "found unresolved violations of cGMP requirements," covered all of the company's quality and production systems, including apparently systems for controlling digoxin tablet thickness.

The inspection generated a Class I digoxin recall on March 31 due to tablet size variation, about a year after the same thing happened at Actavis Totowa.

Caraco's digoxin troubles had begun in December 2008 when the company received a complaint regarding 0.125 mg digoxin tablets that varied in thickness, according to information from FDA's Mission Accomplishment and Regulatory Compliance Services system that the agency released.

The company found that during packaging of the lot involved, the operator had noticed size variation as well. So why had the lot been released? The root cause was determined to be lack of adequate production and lot release controls.

In its June 25 announcement, FDA said the seizure "is intended to lead to major changes at Caraco's facilities."

Caraco's Stray Tablets

Caraco's digoxin tablet thickness crisis came amid growing concern at FDA regarding foreign tablets due to inadequate line clearance and cleanup at the company's Detroit, Farmington Hills and Wixom, Mich., facilities.

The foreign tablet issue figured prominently in the Oct. 31, 2008, warning letter and was the main focus of a Dec. 11-22, 2008, inspection described in a redacted Establishment Inspection Report that FDA later posted on its website.

The report noted numerous instances where authorities signed off on line clearance/cleanup operations that turned out to be incomplete, so that stray tablets from previous runs could become intermingled with tablets from later runs.

FDA investigators took note on the morning of Dec. 11 when they happened across a misaligned machine pouring zolpidem tartrate tablets onto the floor instead of into the bottles that were not quite directly underneath.

Of special concern to FDA: Even though the line was halted, affected bottles removed and adjustments made, no one noted the incident in the packaging record after completing the run - and Caraco later received complaints of incorrect tablet count for that lot.

A later Class III recall of a variety of products due to a lack of assurance that they did not contain additional drug ingredients was probably connected with the line clearance issues.

Clarcon's Contaminated Antimicrobials

Although with Caraco, FDA may have gone more quickly from warning to seizure than before, it subsequently took action against two companies without any warning letter at all.

When FDA investigator Matthew Dionne inspected Clarcon Biological Chemistry Laboratory Inc., Roy, Utah, from April 28 to May 4, 2009, he saw a facility that was lacking in basic features of a drug cGMP program.

There was no quality control unit. The owner and president, Omar Bonada, told Dionne that he was solely responsible for both quality and manufacturing, according to the Form 483 report of inspectional observations, a redacted version of which FDA subsequently posted online.

There were no procedures for process, equipment and laboratory methods validation. There were no master production and control records. Batch records existed but were missing vital information.

There were no written procedures for anything, no stability testing program, no samples retained from any lots, no equipment records, no maintenance procedures, no labeling procedures and no complaint-handling process.

Also if a lot needed to be recalled, there was no way to find it because the distribution system was so deficient.

And it turned out that many lots needed to be recalled. Analysis of several samples taken during the inspection showed high levels of disease-causing bacteria in antimicrobial skin sanitizers and skin protectants.

Although FDA often republishes manufacturers' recall press releases on its website, it went a couple of steps further in the Clarcon case.

The agency issued its own press release announcing the recall on June 8. Also, in the body of FDA's press release, the agency explicitly told consumers to put all Clarcon products out with the trash because of contamination by bacteria that "can cause opportunistic infections of the skin and underlying tissues. Such infections may need medical or surgical attention, and may result in permanent damage."

By Aug. 1 - less than three months after the inspection - U.S. Marshals had descended on the Clarcon facility at FDA's request and seized all skin sanitizers and skin protectants, including ingredients and components.

FDA explained in a press release that day that it requested the seizure after Clarcon did not promptly agree to destroy the materials.

Injunction Shines Light on Teva Animal Health

As with Clarcon, FDA moved swiftly on enforcement, skipping the warning letter process after inspecting the St. Joseph, Mo., manufacturing facility of Teva Animal Health Inc., formerly IDX Animal Health Inc.

On July 31, a little over three months after completing the inspection, FDA announced the filing of a consent decree of permanent injunction prohibiting the company from manufacturing veterinary drugs until FDA agrees that it has achieved compliance with cGMPs.

Teva Animal Health will have to pay daily fines of $20,000 for any consent decree provision it violates and $25,000 for any shipment that violates the decree, up to $7.5 million per year.

FDA described the Feb. 23 to April 21 inspection of Teva Animal Health by four investigators and a chemist in a Form 483 report that the agency redacted and posted on its website.

The report highlighted some key observations that were repeated from the previous investigation in January 2008:

· Failure investigations did not extend to other potentially affected lots;

· There was a failure to follow procedures; and

· Employees were performing GMP functions without adequate training.

In general, FDA said the quality unit failed to monitor and implement quality systems.

There were various large- and small-volume parenterals and tablets that should have been rejected but were not: one lot of thiamine hydrochloride injection contained particles; seven lots of levothyroxine tablets were capped, picked, and had various unexplained spots.

Another problem was that Teva would weigh tablets and capsules in groups rather than individually.

An investigation into foreign material floating in a thiamine hydrochloride injection 200 mg lot should have extended to other drug products associated with the problem.

Similarly, an investigation into high particulate counts for sterile water for injection did not extend to other batches of product.

Also an investigation of complaints about crumbling levothyroxine tablets did not extend to other lots that also had received such complaints until well after they had been released to market.

FDA said numerous products lacked validated processes. Also, Teva had never updated a certain process validation report that had been completed in 1995 by a predecessor company even though different equipment is used now.

A number of product reserve samples had passed Teva's visual exams even though FDA investigators saw that they contained particulates, while some 15 injectables including epinephrine and xylazine had never been tested for particulates.

The "clear, colorless to tinted" appearance specification for praziquantel injection was changed six times over the past few years without any justification or change control. In many cases, the altered specification allowed a pink appearance even though Teva had previously failed batches for appearing pink.

One problem could have been the poor lighting in the retention sample room. But the FDA team came prepared with flashlights.

- Bowman Cox (b.cox@elsevier.com )

Hamburg Promises Quicker Enforcement as FDA Spews Warning Letters

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