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Preparing For An FDA Audit

AIDP

NIE highlights the resources available and pitfalls to avoid so companies are completely prepared when an inspector comes knocking.

In June 2007, the United States Food and Drug Administration (FDA) issued the Dietary Supplement Current Good Manufacturing Practice (cGMP) Final Rule 21 CFR Part 111. In essence, the final rule requires that the proper controls be in place for dietary supplements during manufacturing, packaging, labeling and holding operations.

According to Anthony L. Young, Esq., partner with the law firm Kleinfeld, Kaplan and Becker, LLP based in Washington, D.C., FDA’s overriding goal with cGMPs is protecting the consumer.

“The first goal is consumer safety, and that what is on the label is in the product,” he said. “That is why there is an emphasis on assuring raw materials are identified and free of contamination and that manufacturing operations do not introduce risk to a product through inadequate cleaning, or gloving and hair covers on personnel, for example.”

Michael McGuffin, president of the American Herbal Products Association (AHPA), noted that FDA’s dietary supplement cGMP rule defines “quality” to mean that supplements meet their specifications and are not adulterated. “The agency also enforces the rule to make sure that supplement companies meet all of their cGMP paperwork and recordkeeping requirements,” he said.

More than five years after the rule was established and more than two years past the deadline for all companies to be compliant, Cara Welch, PhD, senior vice president of scientific and regulatory affairs with the Natural Products Association (NPA), has observed the number of FDA inspections increasing dramatically. “Along with more detailed inspections, we also see the agency is willing to use their enforcement tools, i.e., warning letters, consent decrees, injunctions and even product seizure, in order to ‘encourage’ GMP compliance,” she said.

Unfortunately, these increased inspections have revealed that the dietary supplement industry has fallen behind what FDA considers full compliance. Based on FDA’s own assessment, just over 50 percent of the companies inspected under 21 CFR 111 are in full compliance with this regulation. Other companies have either received warning letters or Form 483s that indicate problems or issues observed by FDA agents during inspections.

While the fault for falling short of full compliance may not completely lie with the industry, the responsibility does.

“FDA may have a vision of what fully compliant means, but NPA believes compliance continues to be a moving target,” said Welch, adding that the GMP rule was purposefully written with flexibility to allow companies to find the solution that works for their operations. “Additionally, we know FDA headquarters reviews all reports requiring enforcement, and that the scope and detail of each inspection varies district to district and, even, inspector to inspector.”

In addition, the finalized rule is much more complex than the one it replaced and which has applied to small companies for just over two and a half years, said McGuffin. “There are also certainly still some companies that are not yet sufficiently attentive to the fact that supplement manufacturing has changed dramatically under the cGMP.” 

It is important though to put this industry’s efforts to comply with an entirely new cGMP regulation in context. In a July 13, 2012, meeting with Senator Richard Durbin’s staff to discuss industry compliance with cGMPs, McGuffin expressed AHPA’s shared commitment to increasing conformity to the supplement cGMP. “But I also communicated that a learning curve was completely expected when we changed from the previously required food cGMP regulation to the significantly more complex new rule, and that this learning curve is not uncommon when a manufacturing rule is revised.” 

For example, McGuffin explained that FDA has reported that just 54 percent of seafood companies were in compliance with the new manufacturing rule issued for that industry five years after it was established in 1997. In addition, FDA continues to classify more than one-third of recorded conventional food-related inspections as indicating either “official action” or “voluntary action.”

Still, based on NPA’s interaction with the industry, input from the attendees of NPA educational events and what it sees in its third-party audits, Welch’s impression is that the vast majority of companies are committed to GMP compliance. “However, we still have too many within the industry that are struggling with aspects of the rule.” 

Common Mistakes 

FDA inspectors have observed a wide range of issues during their audits, and after AHPA recently reviewed those inspections, McGuffin offered the following as the top missteps that the industry is making:

. Quality assurance and control issues

. Requirements for quality control

. Issues with recordkeeping requirements. “FDA inspectors noted about twice as many instances related to missing documentation and signatures, etc., than comments about the contents of the records,” said McGuffin.

. Sanitation requirements of the physical plant and associated grounds

. Issues with manufacturing equipment and utensils

. Physical plant design 

Young noted that the common mistakes companies are making stem from them simply not understanding the requirement.

“I believe 100 percent of the major companies, probably 75 percent of the medium-sized companies and 60 percent of the smaller companies believe they are in compliance, but if they have not been inspected by FDA or a good outside consultant, they could be in for a rude awakening. In my experience, people read their compliance with the regulations in their favor,” he said. “For example, finished product testing: instead of testing finished product, testing the blend that is fed into the tableting machine. That is not considered finished product by FDA, that is ‘in process.’ So FDA makes an observation on an FDA 483 form and the company has 14 working days to respond.” 

Welch agreed that understanding the requirement has been difficult for a great many companies, and offered that the majority of the compliance issues NPA has observed over the past few years center around Subpart E—Requirement to Establish a Production and Process Control System. This subpart outlines requirements for quality control operations, specifications, testing requirements and material reviews. “Compliance requires sophistication in understanding the requirements and establishing GMP systems that work for your facility,” she said. “Even companies with strong, wellestablished systems continue to grapple with the nuances of the rule as they address GMP compliance within their unique company structures. There are multiple ways to approach compliance and companies need to determine what works best for their business model while meeting the spirit and letter of the GMPs.” 

Even when an inspector observes any perceived noncompliance and records it in writing on one of the forms used for facility inspections, McGuffin explained that the company still has the power to rectify it. “Once a company is informed of any such observation, it can try to Address the FDA agent’s concerns while the inspector is still on the premises, or it can make any needed modifications promptly and inform FDA that it has done so,” he said.

Resources to Succeed 

A lack of understanding isn’t a sufficient argument when the FDA inspectors are in a facility. As the agency’s efforts to enforce the rule improve, the industry’s role is to educate itself by paying attention to what FDA says publicly and to analyze warning letters or other enforcement actions. According to Welch, these both provide a lot of insight into FDA’s focus and expectations.

Young agreed that this public information is an invaluable tool that companies shouldn’t overlook. “Companies should read every cGMP warning letter that FDA sends out and to ask their quality assurance/quality control people to check the company’s compliance against each warning letter. How would you do on each point?” he said.

Most complex regulations are not always clearly written and subject to various interpretations, and McGuffin noted that 21 CFR 111 is no exception. “Any company that relies only on its own understanding of the actual language in 21 CFR 111 may be able to meet the rule, but AHPA strongly recommends that companies also review all of the publicly available records on supplement cGMP inspections and pay particular attention to any relevant warning letter issued by FDA. This is the best way to understand FDA’s expectations when its agent shows up at your facility,” he said.

In addition, having a third-party GMP audit can be helpful in preparing to meet FDA’s expectation and achieving compliance with these complex regulations. Still, Young cautioned that companies should not expect special treatment or leniency.

“[Companies receiving third-party certifications] do fare better and usually have addressed all of FDA’s major categories of interest. The reason is that those outside audits were done by persons who are carefully monitoring what FDA is doing and use that information in their audits,” said Young. “But I do not believe the industry certifications factor into FDA’s inspection decisions or approaches. When FDA inspects, they inspect on their own terms.” 

NPA has offered GMP education on its own GMP standard for 13 years, and it was the first association to present extensive multiple day GMP seminars, including a session on how to prepare for an FDA inspection, discussion on recent FDA inspection findings and how to appropriately respond to FDA inspectional observations, according to Welch. “We also provide articles and technical papers through NPA and industry publications, allowing attendees to take our information into their companies and implement appropriate action,” she said.

AHPA is another association that has been a go-to resource for the industry even before the final cGMP regulations were published in June 2007. More than six months before, the association produced a seminar to cover the need for companies to establish a quality unit that was outlined in the proposed regulations. This was followed up with additional resources that include:

. July 2007—AHPA conducted a seminar to review the new cGMP rule, which was issued by FDA on June 25, 2007.

. October 2007—AHPA held the first of its “cGMP Compliance Series” seminars, the first covering how companies could begin implementing the new regulations.

. May 2009—AHPA offered seminars covering record keeping, document control and how to write standard operating procedures.

. July 2009—AHPA seminar on how to conduct and manage an FDA inspection

. November 2011—AHPA Teleseminar covering variances

. December 2012 and January 2013— two AHPA sessions on inspections and emerging compliance issues 

For most of these seminars, AHPA produced a written document designed to assist attendees with compliance. All of the seminars continue to be available, so that interested companies can purchase a recording and all of the accompanying materials at the AHPA Bookstore (www.ahpa.org/default.aspx?tabid=344). 

Young participated in AHPA’s seminar series to provide insight on what companies can expect when FDA shows up at a facility, as well as a company’s rights when this happens.

“FDA will ask for anything they want and will be very pushy. I recommend companies get the AHPA guidance or another good up-to-date inspection guidance so they know what their rights are during an FDA inspection,” he said. “You can say ‘no’ where appropriate, and it is important to do so where FDA seeks to go beyond its authority.”

Going Forward 

FDA has clearly indicated, both with its record of active inspection and in public statements, that it expects nothing less than full compliance with the agency’s interpretation of the dietary supplement cGMP regulation by all companies that manufacture, package, label or hold supplement products.

Young views the inability or unwillingness to meet compliance as changing the landscape of the industry.

“Companies that realize they cannot meet cGMPs will probably move their manufacturing to third-party contractors and maintain their marketing arms. But companies that demonstrate noncompliance will be sued by FDA,” he said, noting that the agency has already entered into two cGMP consent decrees with dietary supplement manufacturers this year and has a lawsuit pending against a third. “FDA wants compliance and will not tolerate smoke and mirror responses from companies.” 

Welch advised that as FDA audits continue to increase in frequency as well as its use of enforcement actions, companies have to be prepared.

“FDA’s expectations over the next year will involve asking the ‘next question,’ meaning companies should expect their FDA inspectors to go beyond asking the basic questions and start delving deeper,” she said. “For example, in the past when evaluating identity testing, an inspector may have asked, ‘Are you doing identity testing?’ Now you can expect questions that begin with: ‘What instrumentation are you using?’ ‘How are you sampling?’ ‘How are you compositing your representative sample?’ and ‘What reference standard are you using?’ Companies need to be prepared to answer the next question.”

And the best way to prepare for this is to get procedures in place now, not when FDA inspectors come knocking, according to McGuffin.

“The best suggestion that I can offer is for every company that manufacturers, packs, labels, or holds dietary supplements to establish a standard operating procedure (SOP) for conducting an inspection before an FDA inspector ever arrives. Such an SOP can define, for example, the roles and responsibilities of key staff, records availability, policies on photographs, and any number of additional details,” he said. “The worst thing you could do would be to make it up the first time you are inspected.”

Welch concurred, adding that companies should have identified and trained personnel that will accompany FDA during the inspection, and they should hold mock inspections to ensure they understand how to effectively interact with FDA, she said. Once the inspection is complete, companies should educate themselves, or bring in outside expertise if necessary, to appropriately respond to any 483 observations that are an outcome of an FDA inspection.

“What companies want to avoid,” Welch said, “is allowing observations to escalate into warning letters or other enforcement action.”

Third-Party Preparation

NHK Laboratories Inc. was first GMP certified through the NPA in 2001, at the order of the California-based company’s president, M. A. Karim. “NHK Laboratories has always been dedicated to providing consumers with excellent product quality,” said Shabbir Akand, vice president of sales and marketing. “[Karim] felt that third-party GMP certification would be helpful in identifying opportunities for improvement in our organization so that we could maintain compliance with FDA regulations.” 

A company that specializes in the manufacture and package of two-piece capsules, tablets and powder drink mixes, NHK sees improvement as an ongoing process, and has pursued numerous certifications in addition to achieving FDA CGMP certification for its two facilities, according to Akand.

“We were well prepared for the FDA inspection. We are constantly working to improve our manufacturing processes and maintain regulatory compliance. Due to our previous efforts in acquiring GMP certifications from NPA and NSF, we did not have to do additional work to qualify for the FDA’s parameters,” said Akand.

The greatest challenge NHK encountered was laboratory testing, but it prevailed by investing in analytical equipment and hiring qualified laboratory personnel. “Our quality staff and FDA consultants were invaluable in assisting us throughout this process,” Akand said.

Going forward, Akand predicted that the FDA will hold the dietary supplement industry to a higher standard than the pharmaceutical industry. “Less than half of all Americans regularly take some type of prescribed medication, but a majority of Americans take dietary supplements on a daily basis. We feel this places an important responsibility on our shoulders to manufacture quality dietary supplements,” he said, noting that when one takes into account NHK’s quality management system (QMS) and its staff of qualified professionals, “we believe that NHK Laboratories, Inc. is prepared to meet or exceed the FDA’s expectation.

“NHK believes the FDA was indifferent to our NSF and NPA certifications. However, we feel that these third-party certifications are very useful to us for maintaining regulatory compliance and for facilitating continual improvement, and suggest our [industry] colleagues acquire third-party certifications,” Akand concluded.

Seizing a Transparency Opportunity

Trace Minerals Research (TMR) was one of the first 50 companies to attain NPA (then NNFA) GMP certification, which it still maintains. This has proven invaluable for the Utahbased company, which has been compliant with FDA GMPs since 2007. However, the association’s requirements didn’t completely prepare the company for the government’s rules, according to General Manager Ryan Fisher.

“We felt like we had a solid foundation in place for the FDA GMP certification process, but soon learned that there was much more to be done when preparing our company for the FDA process,” he said. “The cost and effort in going from NPA certification to 21 CFR 111 was significant and took three years to be fully compliant. We did not anticipate the amount of time and money that were required to become compliant and felt that the FDA grossly underestimated the impact of the new regulations on small- and mid-size companies.” 

A finished product manufacturer and raw material supplier, TMR’s attitude toward GMPs and its willingness to communicate it to customers has helped the company to forge stronger relationships.

“It was very important for our customers to know that the quality of products that we maintain could be validated by a third party. In some cases, GMP certification has led to more questioning, but we have tried to be transparent with our customers and let them know of all of our efforts, including areas that have needed improvement. That has led to a great amount of trust from our customers and has proved to be critical in our relationships with them,” said Fisher, who noted that the company is promoting its GMP compliance in literature, on its labels and website, trying to educate customers on how much has gone into the process.

“Many of our customers have been unaware of the extent that compliance entails and have been surprised at the amount of money and time manufacturers have been required to invest. Sharing this information has been helpful in their efforts to educate consumers.”