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GMPs: One Year Later

AIDP

As FDA audits have begun, the consensus is that the industry still has a long way to go proving its compliance, but it’s making a concerted effort to reach that goal. 

Setting a three-year timeline for industry-wide good manufacturing practices (GMP) compliance seemed ample, but as it has passed and U.S. Food and Drug Administration (FDA) has begun facility audits, the industry may be further behind than it had hoped. “In 2010, FDA found that 25 percent of the dietary supplement manufacturers it inspected had significant GMP deficiencies and these deficiencies were found in small, medium and large companies,” said Bradford W. Williams, consumer safety officer, division of dietary supplement programs with FDA (College Park, MD). “Many in the industry definitely have work to do.”

This observation is not solely the FDA’s, but it’s acknowledged by the industry itself.

“For companies that already had solid quality systems and extensive documentation procedures in place, they are able to continue and reinforce their good practices,” said Ed Wyszumiala, general manager for NSF International’s Dietary Supplement Certification Programs (Ann Arbor, MI).

“For companies who have relied upon supplier certificates of analysis and perform little or no testing, and did not have documented procedures, coming up to speed with GMPs has been and continues to be a big challenge.”

While the GMP onus falls to manufacturers, they are certainly not “in it alone.” Trade associations are communicating with the FDA to educate the industry, and the industry as a whole has been creating tools and resources so all can reach compliance.

Urgency Meets Ambiguity

Williams offered the most frequently observed violations at FDA-inspected firms:

• Failure to perform required identity testing on incoming ingredients;

• Failure to set appropriate specifications for components and dietary supplements;

• Failure to adopt written procedures as required in the rule;

• Failure to prepare Master Manufacturing Records for manufacture of dietary supplements; and

• Failure of quality personnel to conduct required material reviews and make disposition decisions.

“It is up to the firm to determine how to correct their compliance issues, in some cases corrections can be made on the spot while the inspector is still there,” said Williams.

While FDA identifies the problem, it does not usually provide the solution, according to Michael McGuffin, president of the American Herbal Products Association (AHPA, Silver Springs, MD). “That’s up to the inspected firm. And while there is no set time to correct a cGMP problem, ‘soon’ is always best; and communication with FDA to inform the agency that the problem has been fixed is also encouraged.”

Even as the industry acknowledges companies are coming up short on their FDA audits, the Natural Products Association (NPA, Washington, D.C.) pointed out that increased funding from Congress has allowed FDA to hire and train even more inspectors, which Perhaps has led to some inconsistencies with the process.

“We are hearing reports from companies of some unevenness in audits, with differences among FDA district offices and even among inspectors,” said John Gay, NPA executive director and CEO. “This is not entirely surprising, given that the FDA is still training their inspectors, but it is something to be aware of. It’s in the interest of both industry and the FDA that inspections be consistent.”

“The FDA GMPs are in their infancy. There is still considerable ambiguity about the interpretation of the regulations. FDA is just training their inspectors and their skill levels vary, so we’ll see uneven enforcement for some time,” said Michael Lelah, PhD, technical director for NOW Foods (Bloomingdale, IL). “On the other hand, the FDA warning letters that are being issued are pointing to some manufacturers that are not covering the basics. The warning letters are indicative that some manufacturers don’t understand quality and compliance.”

Frank Jaksch, CEO of ChromaDex (Irvine, CA), a contract analytical laboratory, offered that difficulties may stem from manufacturers’ inexperience with ingredient identity and adulteration testing coupled with terms that are loosely identified by the FDA.

“For example, all materials going into finished products must meet 100 percent identity confirmed through analytical testing. FDA says to use ‘scientifically validated methods.’ The problem is it doesn’t specify the method,” he said. “It gives manufacturers flexibility to choose methods they want, even if inappropriate. Everyone has seen a single sample produce different results based on the analytical method used. It’s a contentious area now—some issues we’re seeing in the market, such as adulterated supplements, argue whether appropriate methods are being used.”

Another area of concern for the industry to be aware is over finished product testing. “GMPs state that you need to test your finished products, and a lot of companies aren’t,” said Jaksch. “We’re hearing some companies have received guidance that they don’t need to test finished product if The ingredients have been tested through the [manufacturing] process, and that’s a problem. There has been a strong push recently from the FDA to go after finished product testing.”

Third-Party Certifications

The natural products industry has pushed for GMPs for some time, as Dr. Cara Welch, NPA vice president of scientific and regulatory affairs, pointed out: “NPA and the industry have long supported self-regulatory efforts, and the industry wanted GMPs to be included in DSHEA. To help fill the gap between the 1994 signing of DSHEA and 2007 publication of the GMP rule, NPA launched a GMP certification program in 1999, the first third-party GMP certification program for the manufacturing of dietary supplements and ingredients.”

Although the FDA recognizes NPA, NSF and USP as third-party certifying programs, Williams offered, “FDA has not conducted an evaluation of the effectiveness of third-party certification efforts as they relate to dietary supplement GMPs.”

“We think that the FDA appreciates how the industry has stepped up with voluntary certification, and we believe the FDA respects NPA’s GMP program,” said Gay. “There is no evidence, however, that the FDA gives a pass to companies with voluntary certifications, nor do we expect that they should get a pass.”

Still, Williams acknowledged at this year’s SupplySide East in Secaucus, NJ that “funding limitations and other forces are increasing on FDA to consider third-party audits as means of leveraging our resources. We will explore this subject more once this program is ‘mature.’ The industry is ahead of us on this; [it] even uses ‘seals of approval’ to promote compliance.”

“It is well known FDA can be overwhelmed with the arduous task of overseeing the food, drug and dietary supplement Industry,” said Katherine Bond, director of business development with Cyvex Nutrition (Irvine, CA). “If certain mandates are subsequently adopted by the industry, the FDA can somewhat rely on a self-regulating initiative, which in turn will make their role easier. But in any self-regulating industry the players in the industry have a huge role in proving they can fulfill such responsibility by making good business decisions.”

Better Prepared

While receiving a third-party GMP certification is in no means a guarantee a company will pass its FDA inspection, many have seen these programs as invaluable tools in preparing their operations.

NOW Foods has been GMP certified through NPA since 2000. Even more relevant, according to Lelah, would be the recertification process that occurred a couple of years ago with the new FDA Dietary Supplement cGMPs, as NPA adopted new standards. Lelah reported that this required many changes to his company’s documentation and to its testing and production procedures. “It’s important to understand that cGMP processes are continually being refined and improved,” said Lelah. “In our case, our NPA Certification was totally irrelevant to the FDA, as if it did not exist. However, our decade of experience meeting NPA GMP requirements meant it was less burdensome for NOW to prepare for FDA GMP inspections because we have been continually improving our GMP processes over many years.”

Similarly, Nutrition Formulators, Inc. (Miramar, FL) sought third-party certification, but through NSF. Adolfo Graubad, CEO, explained that GMPs forced the company to rethink all its processes. “A company should never become complacent, and we began asking ourselves ‘Can we improve this process? Can we streamline that process? Can we initiate a system of checks and balances for this procedure?’” he said, adding that laboratory services was one of the biggest challenges the company faced. “We overcame it by building a new facility and making a substantial investment in our QA/QC departments and our laboratory equipment.

“We’re very proud of our new facility and our NSF certification,” said Graubad. “As a tool for preparation of an FDA audit, you can’t ask for much more than going through third-party certification.”

Robinson Pharma, Inc. (Santa Ana, CA) attained its first third-party GMP certification since 2005. In 2008, Robinson Pharma was certified as compliant with STR’s (then known as Shuster Labs) Retail Qualification Program. The company has maintained this certification and received a Certificate of Conformance with 21 CFR Part 111 in 2010 and 2011. In March 2010, it received NPA GMP certification, and received USP DSVP certification for its omega-3 fish oil products in April of 2011.

“The achievement of initial certification and our company’s process of continually applying for (and receiving) increasingly rigorous certifications demands a company-wide commitment to quality as a unifying organizing principle,” said Kenn Israel, Robinson Pharma’s vice president of marketing. “The company owner is completely committed to the process as evidenced by substantial investments in hiring and keeping qualified staff, adding many additional quality team members, upgrades and changes in manufacturing practices, improvements in our infrastructure and equipment, and a multi-million-dollar investment in laboratories and analytical equipment.

“As we have not yet been the subject of an FDA audit for 21 CFR Part 111 compliance, it would be arrogant to say we comply fully (to paraphrase FDA’s Brad Williams, ‘We have not yet found a perfect facility’),” he added. “This said, compliance has impacted every aspect of the business and how we operate.”

Meeting Challenges With Resources

“Every inspection that FDA conducts provides a training opportunity for every other company,” said AHPA’s McGuffin. “AHPA has programs in place to make sure that we are accessing and reviewing all of the inspection records, and companies should always feel free to contact me to discuss this important information.”

The AHPA “Did You Know?” program communicates on a weekly basis via e-mail with its members to call attention to one specific detail of the cGMP rule. Its goals were twofold: to make sure that members are paying attention to the details and to remind members that AHPA is a resource. “Our initial expectation was that smaller companies would be more interested in the information provided through this program, but in fact we have fielded as many comments from large companies as from small ones,” said McGuffin.

In 2009, NOW Foods realized that in order to meet the new FDA GMPs, it would need a method to test its raw materials for adulterant drugs (steroids, ED drugs, weight-loss drugs, etc.). Lelah explained how current methods utilize LC-MS, which is very expensive and not conducive to release of incoming materials in a fast-paced manufacturing environment. “In response, we developed an FT-IR rapid screening method,” he said. “We started using this analytical method on all sports and other potentially contaminated ingredients in January 2010. The method was published in a peer-reviewed Publication in October 2010.” NOW Foods shared the method with FDA, AHPA, NPA, the American Botanical Council and National Institutes of Health with the hopes the industry would consider using the approach.

While shelf life dating is not required by 21 CRF Part 111, if expiration dates or voluntary claims such as “best by” or “use before” appear on a nutritional supplement label, FDA officials expect supporting stability test data to be available and will look for this information during GMP inspections. In January of this year, NSF offered the dietary supplement companies the opportunity to be proactive by using its Stability Testing Guideline to verify their expiration dates are backed by sound science.

Looking Ahead

Going forward, the FDA has a clear idea of where it would like the industry to be.

“FDA takes compliance with the Dietary supplement GMPs seriously and expects the industry to do the same. A firm’s operations should be designed to ensure that it is in compliance with the regulation and if it is not, then it must invest the time and effort to come into compliance and stay in compliance. They need to make sure that all necessary GMP measures are in place and being followed consistently,” said Williams. “It’s also important to remember that GMPs are the minimum safety standard a manufacturer must meet in order to ensure its product is not adulterated, and hopefully a manufacturer is looking at ways to continually improve the safety and quality of their product, utilizing appropriate preventive control measures.”

Israel, like many others, said he recognizes there’s still work to be done, but knows the industry will be better for it in the end.

“The industry has a lot of work to do with improving ingredient quality and developing better and more efficient means of testing for identity, purity and potency in ingredients. There is a lot of work yet to be done in the areas of adulterant and contaminant testing and identification,” said Israel. “I am, however, optimistic in that the greatest critics of regulation warned that regulation would decimate the industry. One year later, the industry is here, it is arguably healthier, probably makes a better product than it did last year, it knows its products (and ingredients) much better, and the general public is perhaps a little less afraid in that they know we are being closely supervised.”