Pharmaceutical companies are striving for compliance. Although the number of warning letters issued by FDA during the past five years has declined, companies have begun to feel pressure to better maintain their manufacturing facilities and have started examining their processes to address risks and cut waste. In addition, companies are starting to make an effort to keep their senior managers abreast of the manufacturing operations, something experts say has been lacking in the past.

Although the manufacturing of pharmaceuticals is inherently complex, some companies will face even more difficult challenges as they branch out into biologics. Companies will be on a learning curve as they deal with products derived from living organisms as opposed to chemical compounds. In addition, chemical manufacturing plants will need total overhauls if these plants are to house biologics development. The learning process could pose problems for manufacturers from the outset.

FDA is focusing more sharply on the issues of manufacturing and drug safety, most notably revising the agency’s good manufacturing standards to be more risk-based. FDA’s Current Good Manufacturing Practices for the 21st Century initiative has been lauded by experts. In addition, the agency instituted a new drug labeling program to make risk information more readily accessible to patients and health-care providers.

The revision of the manufacturing practices comes as the number of warning letters issued by FDA for violations of federal requirements has fallen. A report issued by Democratic staff of the House’s Committee on Government Reform noted that the number of warning letters issued between 2000 and 2005 has declined 50%. Meanwhile, seizures of mislabeled, defective, and dangerous products decreased 44%. The report’s authors did not attribute the decreases to increased compliance by manufacturers, because the number of violations observed by field staff has remained relatively constant.

Among the deviations observed during the inspection were the failure to keep separate equipment and supplies that could be exposed to any potentially pathogenic agent from equipment and supplies used in the manufacture of products to the extent necessary to prevent cross-contamination. FDA found the Fluzone production floor, which connects directly to the sterile gowning suite used for sterile processing and to the equipment air lock for passing equipment in and out of the sterile filtration room, did not provide for adequate segregation of early production materials from materials used in sterile processing.

In addition, Sanofi Pasteur (sanofipasteur
.us) failed to establish a system for maintaining equipment to control aseptic conditions, to follow appropriate written procedures to prevent microbial contamination of drug products purporting to be sterile, and to ensure that errors are investigated by the quality-control unit. The company failed to follow appropriate written procedures designed to prevent microbial contamination of drug products purporting to be sterile.

FDA additionally found that the company did not establish the accuracy, sensitivity, specificity, and reproducibility of test methods; 11 analytical methods had not been validated or qualified since Sanofi Pasteur’s 2001 commitment to validate or qualify all test methods. The company also failed to report any event and relevant information associated with the manufacturing of a licensed biological product that represents a deviation from current good manufacturing practice, applicable regulation, applicable standards, or established specifications that may affect the safety, purity, or potency of a distributed biological product.

"Companies need to take a very systemic approach," Ms. Fritz says. "The agency and the industry are now going toward a very modern quality system approach. If companies truly understand and are able to implement this approach, they will eventually end up with a very sustainable quality system and, by default, be in compliance with good manufacturing practices."

Senior-management involvement in quality oversight has been lacking, experts say. Whether being shielded from potential problems or being too far removed from the entire process, upper-management personnel are often the last to know about problems at their company’s manufacturing plants. Many times, an FDA citation is the first management hears about a problem.

"There are far more moving parts that can go wrong, and the standards have evolved from the time that certain plants were built," Mr. Kridel says. "Many of the standards are not physical, they are paperwork. Some companies have had physical compliance problems, others have had documentary compliance problems. The industry should clearly distinguish between the two."

"Once you start integrating a company within your own system, you have to have a difference in culture and a different approach to compliance," Mr. Smit Sibinga says. "As you go through mergers and acquisitions, your governance of the organization becomes more complex."

Mr. Smit Sibinga believes that managers are trying hard to address compliance issues and to produce safe, effective products. The business environment, however, makes achieving that goal extremely difficult. In the time needed to bring the smaller companies into the fold, the larger company is vulnerable.

"If an auditor comes in and discerns that a new set of standard operating procedures apply, but that the organization is still working with the old set, you’re out of compliance," Mr. Smit Sibinga says.

Some companies are beginning to embrace new ways of addressing compliance. But, there is still a degree of hesitancy for an industry that, while constantly evolving, can be resistant to change. The changes necessary to be proactively compliant are difficult as they would involve a change in the company’s culture and thinking. Mr. Breggar says changing any process is difficult, and that is a primary reason why companies stay with their usual methods, even though they may be flawed. In addition, companies tend to look at compliance as the cost of doing business rather than seeing compliance as a means of producing a better quality product.

Balancing business and compliance makes the process even trickier. Mr. Breggar says companies must balance the needs of their shareholders with the regulations of the government, making strategic planning a daunting task and something to which the industry is not accustomed.

"That is just not the nature of the beast, unfortunately," he says. "This industry grew up with a set of requirements, and then another new requirement comes in and it just gets thrown on top."

According to Mr. Breggar, adhering to the regulations in this way leaves companies more vulnerable to non-compliance. "You’re making it more complex and you’re creating a greater chance that one thing that you do disagrees with another," he says.

"More people are becoming aware of the quality approach that, in the past, a lot of people in the pharmaceutical industry and other industries had thought were just fads," Mr. Singer says. "In reality, they are helpful, strategic tools to use."

Companies have begun looking to Lean, a modified form of Six Sigma, to determine what changes will bring the highest value and be the most sustainable. The tools of Six Sigma, Lean, and other continuous improvement methods work to streamline processes and eliminate defects in those processes. Lean is focused on streamlining processes and eliminating the steps that add no value to the end result. Six Sigma provides companies with a philosophy and a set of tools to implement the changes deemed necessary.

Some experts say the process evaluation concepts of Lean and Six Sigma are some of the more effective ways to rein in the complex problems of the manufacturing process. For the pharmaceutical industry, however, many of the concepts would have to be altered to reflect the imperfect nature of developing and manufacturing prescription drugs.

Pure Six Sigma is being used less because the tool is based on the goal of having zero failures, which is extremely difficult to attain with small-molecule drugs and biologics. Mr. Singer says scientists do not look to reduce variation because a positive breakthrough or discovery may be rejected.

Using the principles of Lean and Six Sigma can be one part of the equation when evaluating the process, but will not fix the core problems. "They are not strategies, they are not tactics, they are tools," Mr. Smit Sibinga says. "Lean and Six Sigma do not necessarily address corporate systems. You can use them to improve your corporate systems, but they’re not the answer in themselves."

The surge in companies exploring biologics will create exciting opportunities for new business, but will involve a more painstaking and difficult development process. In addition, getting involved in biotechnology will require completely different manufacturing facilities, leaving companies vulnerable to new compliance issues. Experts believe that companies delving into this area will experience growing pains that will include struggling with compliance.

"Companies that haven’t gotten into the biopharm field before will see the stress of that learning curve, unless they’re starting off with people who have that expertise and can help them jump over the potential failures up front," Mr. Singer says.

Mr. Singer does believe, however, that the initial struggles will ultimately be beneficial to companies in terms of understanding, monitoring, and evaluating the manufacturing process.

Biotechnology companies, in particular, are taking the initiative to address compliance issues. Many of these companies are newer and able to more fully embrace and apply the quality-systems approach.

"They haven’t been around as long as some of the older pharmaceutical companies," Ms. Fritz says. "They’ve tended to grow up more in a quality systems environment. Some of the older companies are still struggling with the concepts."

The good manufacturing practice regulations have been in place since 1978. FDA’s most recent revision does not replace the original set of rules, but enhances them. "It takes a very long time to change the law, so it’s much easier to enhance and put an approach into effect," Ms. Fritz says.

FDA identified six manufacturing subsystems that make up the quality system as a bridge to the old regulations. The six systems are the quality system, the laboratory control system, the production system, the materials system, the facilities and equipment system, and the packaging and labeling system.

The quality systems approach may allow companies to be more in synch with regulations in other countries. Such harmony would eliminate the siloing now in effect, according to Ms. Fritz.

"It’s understandable why this happens," Ms. Fritz says. "Companies are trying to get product out the door, so the manufacturing group is very isolated and works independently of other groups."

Companies need to be observant. By watching their competitors and paying attention to FDA’s actions, companies can address their own issues in the event FDA inspects their facilities.

"Are you, as an organization, able to rapidly and proactively connect the dots?" Mr. Smit Sibinga says. "If your competitor has a problem in a specific area and that’s in the public domain, do you have the capability to execute on that kind of market intelligence? It’s a bit of a cat-and-mouse game, but that helps improve standards time and again. We need to get better and better."

Some experts say the complex nature of FDA regulations contributes to a company falling out of compliance. Following the rules could prove to be as challenging as the manufacturing process itself. The agency seeks to outline guidelines for companies to follow as opposed to creating a rigid checklist so that companies do not limit themselves in continuously improving the process.

She says companies may have trouble keeping up with the evolving regulations. "Over time, standards within the industry change because improvements are ongoing and, unless they’re educating themselves about those things, everybody may not be aware of them," Ms. DeGrazio says.

The difficulty and vagueness of the rules will probably always remain, Mr. Reichertz says. Although the core rules have not changed in almost 30 years, there have been numerous guidances and advisories from FDA, which add to the confusion.

"There’s always going to be a lag; it’s not an easy thing to do," according to Mr. Reichertz. "Even the interpretation of the rules changes over a period of time. The complexity of what you have to do now versus what was required then is a lifetime’s worth of difference."

The quality-control personnel within the companies are sharing information. Contrary to other departments, the companies’ quality assurance and regulatory staff have formed their own network to discuss compliance issues.

"They keep tabs on what the FDA has done across the industry," Mr. Smit Sibinga says. "They’re all very closely connected, and that’s one of the interesting things about that part of the market."

A study released in June by Rep. Henry Waxman, D-Calif., prepared by the House Government Reform Committee’s Minority Office, showed that FDA enforcement action decreased during the last five years while violations have remained stable. The study, released in June, reported that FDA issued 535 warning letters to companies, a 54% decline, compared with 2000 in which the agency had issued 1,154. The decline was a 15-year low. FDA inspectors, however, found about the same number of violations, falling 1%.

FDA’s Center for Drug Evaluation and Research issued 79 warning letters in 2005, 39% less than in 2000. The Center for Biologics Evaluation and Research issued 37 warning letters in 2005, 14% fewer than in 2000.

Meanwhile, the number of "483 forms," which are issued by field inspectors to companies to notify them of the number of violations during an inspection, has increased. In 2000, FDA issued 6,334 of these forms. In 2001, 7,683 forms were issued; in 2002, 7,180 forms; in 2003, 7,814 forms; and in 2004, 7,137 forms. In 2005, 6,286 forms were issued, about the same as in 2000.

In 32 cases of violations between 2000 and 2005 when FDA field inspectors recommended a warning letter be issued, an untitled letter was issued instead. Unlike warning letters, untitled letters do not require a written response, but warn that additional enforcement action would happen if the company did not correct its actions or mandate a follow up inspection. According to the study, this downgrade in enforcement action minimized the violations and lessened the likelihood of voluntary compliance.

According to Mr. Waxman, the seizure of Paxil CR in March 2005 caused his office to dig into the matter of FDA enforcement actions. He notes that the seizure came after FDA noted manufacturing problems at GlaxoSmithKline’s Cidra, Puerto Rico, plant in 2002, 2003, and 2004. In April 2004, FDA field inspectors recommended that FDA order the plant to stop manufacturing the defective drugs.

"It’s a sad but telling commentary that this is what passes for success at today’s FDA," Mr. Waxman says.

Despite the decline in warning letters, Mr. Singer believes that the agency’s 21st Century initiative is evidence that FDA has not become lax. "FDA is diligent in how they inspect, who they inspect, and their approach to inspections," he says. "They’ve developed this risk-based approach and quality-systems approach, but it’s not 100% guaranteed that they’re going to get everything and catch everything."

Mr. Breggar says the study is open to interpretation. He believes that FDA has begun looking more closely at pharmacovigilence and post-marketing programs, a move that is more important than the number of warning letters the agency sends out.

"The company putting more emphasis on data analysis and drug safety benefits me," Mr. Breggar says. "The company paying a fine to FDA doesn’t directly benefit me."

Ms. Fritz believes that the report is accurate and may be contributing to the number of companies falling out of compliance. "Companies may be becoming more lax because FDA’s oversight is not as robust as it has been in previous years," she says.

Mr. Smit Sibinga believes that enforcement has limitations. FDA is getting better at targeting the right companies, which is essential for an agency with strained resources. If FDA sees a problem at one company and thinks that problem could be affecting the entire industry, the agency will go to similar companies and look at the same issue.

"Enforcement cannot be the solution," Mr. Smit Sibinga says. "FDA does not have infinite resources and cannot hit companies on a continuous basis. Like clinical trials, FDA must be following some predictive model as to who they hit and why."

More importantly, experts say FDA needs increased resources. The lack of money and inspectors is a contributing factor in the compliance debate. "You can’t overstress an organization otherwise a lot of other things are going to fall by the wayside," Mr. Singer says. "If they’re going to pass that type of legislation so that it can increase the resources, money, and people for FDA, then so be it. A good organization should be able to deal with having more resources."

Mr. Reichertz agrees that FDA needs more financial resources, particularly to handle post-marketing studies and to have the personnel to run those programs and process the amount of information submitted. A bigger issue, he says, is the lack of feedback the agency receives from physicians and health-care providers regarding adverse effects. Although he is doubtful about the effectiveness of the bills, Mr. Reichertz believes that the government should initiate programs to encourage and train physicians to report better.

"If there were more compliance by the health-care community, you’d find out things a little more quickly and in better detail," Mr. Reichertz says. "That’s the problem, and it’s very difficult to see how you force that through federal legislation."

Mr. Kridel believes that companies have difficulty creating incentive programs to have doctors do the work needed for post-marketing surveys. He says some companies have been diligent about the surveys and have received cooperation from doctors. Others have been diligent and have not received cooperation.

"You get every possible combination out there," Mr. Kridel says. "It’s hard to get the overworked docs to fill out even more papers."

The complexities and challenges associated with achieving compliance will always be part of the problem. Companies will have to be ever-vigilant as FDA’s standards, regulations, and requirements continue to evolve within the constantly changing industry. Making the lines of communication clearer and more direct within the company structure, keeping on top of the manufacturing process, and being aware of FDA’s revisions and guidances are some of the basic ways to exert some control of the quality processes. Like adhering to the rules themselves, these goals are difficult to master and achieve.

Mr. Singer says more information needs to be shared so that the industry is on equal footing with regard to following the intricate rules. "The pharmaceutical industry is mainly science-based and very competitive," he says. "It’s one of those things almost every other industry that is involved with quality has been able to share — what they do, how they’re using things, and whether they’ve been successful. In the pharmaceutical industry, there has been more hesitation in doing that. There would be some benefit if people could provide a level playing field."

Mr. Smit Sibinga believes that, across the entire global industry, the goals are the same, as are the difficulties. "FDA, the European agencies, the Japanese Department of Health, and each individual company are all after the same thing: making the best product, the safest product, and the most effective product possible," he says. "There’s not a single person in any of these industries that is not attempting to get there. There are just incredible complexities."