FDA Lawyers Blog

by Elizabeth Murphy

The European Fine Chemicals Group ("EFCG"), a sector of the European Chemical Industry Council ("CEFIC"), and the Society of Chemical Manufacturers and Affiliates ("SOCMA") have urged FDA to take a more active role in the regulation of foreign API manufacturers. Citing, among other reasons, "[t]he accelerating globalization of the industry," as well as "[t]he slow pace of adjustment by governmental bodies charged with oversight . . .," the comments submitted by EFCG and SOCMA advocate both improvements to the current compliance and oversight regime and a publicly-accessible database that would hold noncompliant entities accountable.

EFCG and SOCMA are lead trade associations in Europe and the United States, respectively. EFCG is a sector of CEFIC, which represents 29,000 companies and accounts for one third of the world's chemical production. SOCMA represents approximately 300 companies and encompasses over 2,000 manufacturing sites. Members of both trade groups manufacture APIs, excipients and intermediates.

FDA recently opened a second comment period in relation to its generic drug user fee plan, which aims to expedite review times for generic drug applicants through the collection of user fees. CEFIC and SOCMA posit that (along those same lines) all API manufacturers, particularly foreign manufacturers, whose products enter the U.S. market should submit to FDA inspections on a regular basis. In order to fund said inspections, FDA should impose registration and inspection fees for all relevant API manufacturers. The proposal further envisions a comprehensive online database that would make GMP certificates publicly available, similar to the EudraGMP database run by the European Medicines Agency.

The proposal aims to promote public safety, but also to level the playing field amongst API manufacturers. Due to the challenges inherent in increased inspections of foreign facilities (see our previous blog on the topic here), API manufacturers are thus incentivized to establish operations in areas where inspections are less frequent. EFCG and SOCMA submit that their proposal "would be a giant step forward in rebalancing the competitive environment." Both trade groups have expressed willingness to comply with the measures they propose.

by Howard E. Rosenberg, Ph.D.

At the recent Pew Health Group Conference John Taylor, FDA's Acting Principal Deputy Commissioner, told the attendees, "[A]nother public health crisis like Heparin seems inevitable." This being largely due to the fact that not enough foreign inspections of pharmaceutical active pharmaceutical ingredient ("API") manufacturers are being carried out. The cost of implementing and maintaining current good manufacturing practices ("cGMPs") at API plants is significant and for the past few years several groups representing API manufacturers that comply with cGMP have been lobbying hard to level the playing field.

The number of foreign manufacturing plants had grown to more than 3,500 in 2008, from roughly 1,200 in 2001 - a 185 percent increase. In 2001, 20.7 percent of facilities were inspected, but only 8.9 percent in fiscal year 2008 i.e., depth of the problem can be highlighted by the fact that there are nearly 1,000 manufacturers of drug substances eligible for FDA inspection in China alone.

At the conference several suggestions were raised which were designed to help improve the frequency and quality of API plant inspections. One suggestion was for FDA to consider using certified private inspectors with experience to carry out inspections. Another idea was that the agency should develop a system to provide a publically available plant rating scale for manufacturing sites. Brant Zell, who chairs the Bulk Pharmaceutical Task Force, a trade group for API suppliers, stated that the supply chain problem could be improved if FDA were authorized to fine manufacturers and conducted unannounced inspections in India and China. The Society of Chemical Manufacturers and Affiliates has recently asked for mandatory FDA inspections with the sites paying for the cost of the inspections.

Although FDA has moved to halt imports of known violators by issuing warning letters, it was reported that at one site the manufacturer refused an FDA investigator access to its facility. A warning letter was issued, but the episode highlights the limits of FDA's ability to have full access to the documentation and records at foreign facilities. Even where full access is granted, the limited time available for the inspector to carry out inspections (due to cost and limited manpower) may well lead to facilities being given the benefit of the doubt when a more thorough inspection would be appropriate.

by Brian Malkin

On February 16-18, approximately 500 industry executives and stakeholders attended GPhA's Annual Meeting in Orlando, Florida. During the public sessions to which this blog refers, representative generic industry chief executive officers ("CEOs") were somewhat optimistic with the potential for $150 billion of branded products coming off patents (coined a "patent cliff"). Yet the overall message was more negative, focusing on slower FDA approvals, less new innovator targets for generics with greater possibilities for preemption issues regarding failures to add warnings to generic drug labelings, and an uncertain biosimilars market to replace the small molecule opportunities that will be drying up.

Deborah Autor, J.D., FDA's Director of Compliance, Center for Drug Evaluation and Research, announced that the Office of Generic Drug's ("OGD's") more than 2000 application backlog was likely to continue and possibly worsen, in part due to FDA's inability to conduct the necessary pre-approval inspections for new drug applications--both innovator and generic. For example, Autor said that FDA anticipated that in fiscal year 2011, 192 foreign facility inspections will be required, but FDA will only be able to conduct 62. While generic application user fees could theoretically reduce approval times for new applications if FDA adopted a "surveillance model," Autor noted that inspections were a key reason why previous negotiations for user fees failed and could fail again. Autor added that this is compounded by the fact that there are roughly eight times the number of generic to innovator applications, and generic applications tend to have more multiple supplier or facility issues with less available data during inspections. Autor hoped FDA's message that corporate executives are accountable for FDA violations may improve the quality of generic record-keeping, including generic manufacturers obtaining better data from their suppliers.

On the generic industry side, there are greater opportunities for corporate accountability and a mixed bag for continued growth. Current legal trends suggest that leading generic applicants will likely be responsible for failures to add warnings to their products (the preemption issue). While generic growth was higher than total prescription growth (2.3 % versus 1.0%) based on market data, growth in traditional sectors such as cancer treatments were slow and other indicators showed that despite the patent cliff, the branded industry has been slow to innovate, leaving less future generic targets.

by Christopher Gosselin

Color Chart?
Baxter has some work to do at its Jayuya Facility in Puerto Rico, after FDA's warning letter last month cited the facility for several good manufacturing practices violations, including a failure to thoroughly investigate numerous complaints about contamination and discolored products. In September, an equipment failure at the Jayuya facility led to the recall of 17 lots of product, including Clinimix® (Amino Acid in Dextrose), Clinisol® (Amino Acid), and Travasol® (Amino Acid). According to the warning letter, Baxter's investigations did not adequately address the causes of the recalls.

Baxter did implement at least one creative solution in response to the discoloration problem-it distributed a "color chart" to end users explaining when not to use Baxter's products based on product color. Not surprisingly, the color chart failed to amuse FDA. Baxter received a misbranding violation because the approved labeling fails to bear adequate directions for use. It seems Baxter never submitted either the color chart, or any underling analytical data, for FDA approval.

According to the warning letter, Baxter's "investigation concluded that the administering health care professionals (i.e., pharmacist, nurse, or physician) would identify any discoloration and prevent the usage of the drug product." "It is unacceptable," the warning letter continues, "to rely upon the health care professional to fulfill your Quality Control Unit responsibilities." "The end user should not be expected to make a determination of product safety and effectiveness based on a color chart ... [i]t is your responsibility to ensure that your products comply with their predetermined specifications to ensure their quality, safety, and effectiveness."

Although Baxter said that it continues to manufacture the products at issue and that they remain safe and effective if used in accordance with labeled instructions, you might not want to throw your color charts away just yet.

by Howard E. Rosenberg, Ph.D.

Last July, the Drugs Controller General of India ("DCGI"), which is akin to FDA, proposed to implement overseas inspections of manufacturing sites as a consequence of the banning of the import of raw materials from ten Chinese drug companies that supplied products without having the mandatory drug manufacturing standards. It has now been reported that in about two weeks the DCGI will begin inspections of manufacturing facilities from where Indian companies source their active pharmaceutical ingredients and intermediates for pharmaceutical production. The pilot program will initially focus on Italy and China and, if successful it will then be extended and introduced for all countries.

The Central Drugs Standard Control Organisation is already in the process of pulling together a team of fifteen to twenty drug inspectors, trained in auditing and inspection of sites in accordance with international standards.

Dr. Surinder Singh, Drugs Controller General of India, said, "Currently there are 1364 sanctioned posts, and around 864 are filled up. We need at least 3,100 drug inspectors in the country." http://www.business-standard.com/india/news/dcgi-plans-to-raise-drug-inspectors-tally-in-india/417975/ Dr. Singh has already pointed out that there was a need for overseas inspections, saying that it is the responsibility of the indenting agents to make the manufacturers aware of the rules and regulations of the country. "As of now they have poor knowledge of the Drugs and Cosmetics Act, poor understanding and interpretation of the drug rules of the country. In fact, surprisingly at times, even their submissions are not complete. It is the responsibility of the indenting agents to make them aware of these laws and also to ensure that these companies follow the rules and regulations of the country if they want to do business in India."

If successful, India's move to inspect manufacturing sites may lead to greater cooperation with FDA inspectors for pharmaceutical products imported from India.

by Howard E. Rosenberg, Ph.D.

In a letter dated December 15, FDA warned makers of dietary supplements to police themselves and their suppliers and distributors, to ensure that drugs are not included in their products and to follow current Good Manufacturing Practices (cGMPs). The agency asked five trade organizations to do the same. FDA told the makers and distributors of dietary supplements that there are hundreds of products on the market that illegally contain drugs or compounds which act as drugs. Generally these supplements are labeled for weight-loss, bodybuilding and "sexual enhancers" and are illegal, because they contain known pharmaceuticals or similar chemicals, which effects on humans have not been studied or because they contain drug claims.

Although FDA actions have included recall of supplements and referral of companies for criminal prosecution, FDA believes the problem is still not being solved. The origin of the questionable supplements usually is not known, but many of the products come with Chinese writing, suggesting that they are made in China. Most of the questionable supplements are sold over the Internet. Federal law requires that supplement makers be responsible for marketing a safe product and for them to be manufactured to cGMP. The manufacturers don't have to prove the safety or effectiveness of their products.

Following the introduction of the Dietary Supplement Regulation Bill in 2007, the Indian SME segment has been finding it difficult to enter the U.S. market. Owing to this regulation, which requires the products are manufactured to cGMP, the U.S. dietary supplement market is dominated by the large players from India who have already invested in the high level of manufacturing and quality control that the regulation requires. cGMP compliance has up until now been viewed as cumbersome and an expensive exercise for these SMEs. Coincidentally, a recent article in Pharmabiz.com (Dec. 10, 2010) stated that the U.S. dietary supplement market is valued at $25 billion and that Indian Small and Medium Enterprises (SMEs), specializing in the manufacture of raw materials for dietary supplements, are eyeing this as a big opportunity. They are gearing up to obtain the mandatory certifications.

In view of latest FDA's concerns, it appears that self-policing will not be enough to ensure that dietary supplements are both free from illegal substances and routinely manufactured to cGMP.

by Charles J. Raubicheck

On July 21, FDA denied a citizen petition by the drug manufacturer Kremers Urban ("Kremers") (through its law firm Foley & Lardner) that asked the agency to impose more stringent good manufacturing practices (GMP) requirements for: (i) production of highly potent drugs, and (ii) possible cross-contamination during manufacturing operations.

FDA asserted that existing GMP standards, in the Federal Food Drug and Cosmetic Act and related regulations and guidances, are adequate to address these issues, particularly those standards governing specifications and process validation.

The agency rejected the petition's call for new drug application and abbreviated new drug application disapprovals, draft guidances, and advisory committee review.