FDA regulations promise opportunity for contamination-control industry
By Sarah Fister Gale
The Food and Drug Administration (FDA) has been holding out on the nutraceutical industry for years, but that’s all about to change. Nutraceutical manufacturers are anxiously awaiting the long-anticipated regulations from the FDA that will finally give the industry guidance for good manufacturing practices (GMPs).
These regulations, which have been in the making for more than a decade, are expected to be released by June. The regs will create a system of standards for safe manufacturing, which ensure that the ingredients and dosages on the labels of nutraceuticals are accurate, and that finished products don’t include any dangerous contaminants. They will also give the industry and the FDA tools to deal with unscrupulous manufacturers and to build a foundation of consumer trust in products and label claims that have long been difficult to validate.
Nutraceuticals, which are often referred to as phytochemicals, or functional foods, are natural, bioactive chemical compounds that have health-promoting, disease-preventing, or medicinal properties. These products are isolated or purified from foods, and generally are sold in medicinal forms. They typically fall under the “supplement category” and often come in tablet, powder, or liquid form comprising herbs, vitamins, and other nutrients.
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While still considered an “emerging field,” the nutraceutical market currently translates into a $19 billion industry. But despite its size and global presence, the nutraceutical, or supplement, industry has operated without specific manufacturing guidelines from the FDA for years. As a result, there have been repeated incidences over the years in which bottles of supplements were found to contain products with wildly varying dosages and potencies, even among products under the same label from the same manufacturer. And in more ominous cases, there have been incidences in which supplements were found to be contaminated with toxic materials or active pharmaceuticals.
As recently as December 2005, a line of Ginkgo biloba supplements was recalled after tests of 13 bottles showed that three were contaminated with lead. The product was also found to be low in potency based on the amounts of phytochemicals detected.
And in January of this year, the FDA warned consumers not to use two “all natural” Brazilian diet pills, known as Emagrece Sim and Herbathin, because testing had revealed they may contain tranquilizers, antidepressants, and stimulants. Such incidents, while not widespread, are certainly an indication that the time has come for regulations to be instituted.
Food GMPs fall short
Most experts are quick to point out that these incidences of contamination are rare, and suggest that dosage variations, while not uncommon, are atypical of the whole industry. It is one of the reasons why reputable supplement manufacturers are so anxious for regulations from the FDA, notes Andrew Shao, vice president of scientific and regulatory affairs for the Council for Responsible Nutrition (Washington, DC), a trade association of companies in the nutritional supplements and ingredients industries. Shao has found that most companies are looking for a system to validate their own methods and a means to differentiate themselves from the charlatans that give the industry a bad name.
Even though there are no supplement-specific regulations at this time, the industry is not unregulated, Shao points out. “It’s a misperception that we are loosely regulated,” he says.
Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), the dietary supplement manufacturer is responsible for ensuring that a dietary supplement is safe before it is marketed. The legislation defines a dietary supplement as any product that contains one or more dietary ingredients, such as vitamins, minerals, herbs, or other botanicals, amino acids, or ingredients used to supplement the diet.
The legislation maintains the FDA’s authority to safeguard the public against any unsafe product, and states that the FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market.
Generally, however, manufacturers do not need to register their products with the FDA, nor obtain FDA approval before producing or selling dietary supplements, thereby leaving the market open to any company interested in producing products. Manufacturers are expected to make sure that their product label information is truthful and not misleading. Although it’s been 12 years since DSHEA was published, the industry is still waiting for the FDA to publish regulations to support the act, and until then, it is up to the manufacturers to define guidelines for their processing techniques to ensure that their products are safe and meet label claims.
According to DSHEA, until new regulations are released, the industry should model its GMP methods after the GMPs originally established for food processing: Title 21 of the Code of Federal Regulations, Part 110 (21 CFR 110). The food GMPs describe the methods, equipment, facilities, and controls for producing processed food, and act as the minimum sanitary and processing requirements for producing safe and wholesome products.
Exactly how manufacturers are expected to do that, though, has never been clearly defined. Supplement manufacturers are expected to use food GMPs as the minimum requirement but must establish their own methods for implementing them. It’s a good start, but it leaves many gray areas for supplement manufacturers whose products do not function the same way that food functions.
The problem with using food GMPs is that the supplement category falls solidly between food and pharmaceuticals, says Burt Young, senior business development manager for CH2M HILL (Cincinnati), a provider of technical service to the pharmaceutical and biotechnology industry. “Pharmaceutical drugs correct illnesses and have a lot of science to back them up, while food is calorie conversion. Supplements fall somewhere in the middle.”
 Figure 1: Pictured here is Vita-Tech’s George Santana, VP of Production Operations. Photo courtesy of Vita-Tech. ©Christopher Barr Photography. |
Supplements do more than convert calories, but they don’t operate as drugs, which are designed to solve a specific medical condition and are heavily regulated. They have concentrated potent doses of ingredients, making them more like drugs, but their application is more similar to food-as a nutritive or good health benefit. Because supplements are often a complex mix of active ingredients, dosage claims can also be tough to guarantee. “A multivitamin may have 50 active ingredients in a single tablet,” says Shao. “That’s unheard of in any other product category.”
The precise blending required to achieve exact amounts of so many active ingredients takes a great deal of science and technology to perform accurately on a consistent basis. An uncontrolled manufacturing process can result in cross-contamination, low-dosage tablets, or super-potency products that can even be linked to medical conditions, such as blood clots from an overdose of Vitamin K. To avoid these problems, the industry is clamoring for regulations that will guide manufacturers in their processing and quality-assurance strategies, and help validate final products.
“The industry needs regulations of its own,” Shao says, and not just to establish GMPs for manufacturers or create uniform processes. According to Shao, the regulations also will offer validity to an industry that has often been accused of being too loosely monitored, and put a stop to shady manufacturers making audacious label claims about their products’ ability to provide miraculous cures or a longer life. “Regulations would do a lot to bolster the credibility of the industry for consumers, Congress, and the media,” he says. “There’s a stigma when you don’t have your own set of regs.”
The industry gets cleaner
Since DSHEA, many larger supplement manufacturers, which are tired of waiting for the regulations to be released, have voluntarily incorporated more pharmaceutical GMP practices into their manufacturing facilities. These efforts include incorporation of cleanroom areas in lager facilities, filtered air systems, aseptic filling techniques, and cleanroom equipment.
“Five years ago, supplement manufacturing and pharmaceutical manufacturing were a mile apart,” says Greg Williford, vice president of sales and client services for Vita-Tech, a Tustin, California, contract manufacturer and custom maker of private-label vitamins. “Now they are about a quarter of a mile apart.”
Young agrees: “The industry is definitely heading toward cleanroom conditions and enclosed air-control systems.” In fact, he’s seen many clients that previously had no cleanroom environments recently invest in Class 100,000 spaces for their operations. “The most important thing manufacturers are thinking about is keeping the environment clean,” he says. “They are trying to create their own protocols and GMPs to support that.”
Every product has a different set of manufacturing risks, based on a mix of ingredients, raw material sources, and final form.
For example, tablets are handled almost exclusively in a closed manufacturing operation and, therefore, they are only exposed to machine-generated contaminants, while powders tend to be handled in a more open environment and are more easily exposed. Some raw materials are derived from animals, such as fish oils or the chondroitin that comes from the tracheas of cows and pigs. These need to be handled and tested differently from agricultural products or minerals.
Manufacturers that purchase from overseas suppliers are also challenged to ensure that they use appropriate quality-assurance strategies in their facilities to guarantee product purity and consistency, Shao says. He notes that many larger firms purchase the farms where their raw materials are produced to “control quality across their supply chain.”
Manufacturing risks
For all nutraceutical products, the biggest initial environmental concern is airborne contaminants, such as oil, lubricants, spores, and proteins in the areas where raw material is handled. If airborne contaminants reach a certain level, they can impact the potency of a product, Shao says, which is why more companies are adding cleanrooms, separate gowning areas, and air-filtering systems to protect raw ingredients from environmental hazards prior to processing. “Air quality and air cleanliness is a big issue for this industry, which is why we support GMPs.”
In older facilities, moisture can also cause concerns, says Walter Czander, principal technologist for CH2M HILL Lockwood Greene (Atlanta). “If you don’t get rid of humidity fast enough, mold can grow, which causes problems.” To battle mold and other environmental contaminants, Czander has seen a movement in the industry to upgrade processing environments. Companies are adding seamless vinyl floors and epoxy-coated walls for easier cleaning, and airflow systems in front of doors with sweeps on the back end to better control airborne contaminants. “These firms realize they have to build rooms they can easily clean. But money is always a factor,” he adds. “It’s a bottom-line business.”
Once the ingredients enter the processing stage, food GMPs are followed in order to manage risks. These include strategies such as cleaning and sanitizing equipment prior to processing, and verification (through microbiological test swabs) that surfaces and equipment are clean. Most experts agree that once processing has begun, food GMPs are applicable for the supplement environment. They believe that if the formula and processing techniques are adhered to, manufacturers can be confident that the product is safe and its purity isn’t compromised.
However, when the product is finished, packaging is another critical control point where supplements can be at risk for contamination because they are exposed to open-air environments, Williford says. “This is always interesting, because you have to determine where processing stops and packaging starts.” Again, cleanroom conditions can help alleviate risks by keeping products in an isolated environment until they are sealed.
Larger manufacturers can’t wait
Companies like Vita-Tech, which manufactures products for 100 companies in 35 countries, say they can’t wait for the FDA to put forth regulations. The larger companies that work with major distributors and retailers fall under regular scrutiny from clients and undergo frequent internal, commercial, state, and federal audits, as well as random retention samples, to prove they can trace every product through its life cycle. “The big retailers don’t take the manufacturers’ word for it; they conduct substantial audits to verify every facet of manufacturing control,” Williford says.
To ensure it meets the demands of its clients, Vita-Tech and other major manufacturers carry drug-manufacturing licenses even though they don’t manufacture drugs-just to add credibility to their process. “It adds a layer of reassurance to the client’s well-being,” Williford says.
Vita-Tech also uses cleanroom conditions in its facilities, and has a full in-house microbiological lab to run tests to verify the sanitation and purity of its environment and ingredients. It adheres to the United States Pharmacopoeia for stability testing, and tests every batch of ingredients for E. coli, yeast, mold, staphylococcus, and salmonella, as well as evaluates its purity and compliance. The company retains samples of all ingredient lots for traceability and tracking.
Vita-Tech reduces its analytical and documentation costs through the use of high-capacity equipment and uniform processing. This includes a custom-made 20,000-pound capacity blender and continuous coaters that can handle up to 15 million tablets per day.
“The ingredients in our product are weighed and electronically measured to ensure a homogenous mix for every tablet, capsule, and powder, every time,” Williford says.
To further protect its processing environment, Vita-Tech also focuses heavily on employee screening, conducting drug testing and background checks, and putting staff through annual GMP training.
Setting its own standards
Other companies seeking ways to improve their operations and corroborate their efforts have relied on organizations such as the National Nutritional Foods Association (NNFA; Washington, DC), which created its own voluntary GMP regulations and certification process for supplement makers in January 1999. All NNFA members have the option of using this third-party certification process, which evaluates issues such as record-keeping strategies, sanitation protocols, documentation of standard operating procedures (SOPs), raw material handling and identity testing, and expiration-date use. “Our audit process is similar to those done for drug manufacturing,” says Carl Reynolds, an NNFA GMP auditor and senior consultant for AAC Consulting Group, which is a subsidiary of Kendle International (Cincinnati), a leading global clinical research organization and a regulatory consulting agency for industries regulated by the FDA.
The NNFA alone sent 50 pages of comments to the FDA on proposed regulations, and offered its certification process as an example. “We believe whatever the regulations are, it will be a less-painful transition for our members who have gone through our certification process,” says David Seckman, NNFA’s executive director and CEO. “We hope that the FDA will take what we’ve learned over the years into account.”
Regulations on the way
It appears Seckman and the rest of the industry won’t have to wait much longer for answers from the FDA. After more than a decade of anticipation, thousands of pages of comments from industry experts and trade associations, and months of comment periods, the FDA is finally expected to release the regulations for supplement GMPs sometime this year.
Two months ago, on January 16, the Office of Management and Budget (OMB) cleared a draft notice of proposed rulemaking (NPR) on dietary supplement GMPs, which, according to an FDA spokesman, would appear in the Federal Register “in about two weeks.” That means, optimistically, the final regulations could be released before June. The industry is abuzz with speculation on what the final document will include, and those willing to speculate say the new regulations will certainly be far stricter than those guiding food processors.
While lots of manufacturers have already implemented many of the strategies likely to be covered in the regulations-such as expiration dates and record keeping-there are fears across the industry that if the regulations are loaded with final product-testing requirements, it could cost many companies a lot of money and put some manufacturers out of business. For example, initial indications, based on a proposed rule offered by the FDA in 2003, suggest the agency will not accept Certificates of Analysis (CoA) as proof that those raw ingredients meet label claims (meaning manufacturers would have to test every batch of ingredient before processing. Many in the industry hope this is not part of the final regs.
 Figure 4: An employee inspects the packaging process at Vita-Tech. Photo courtesy of Vita-Tech. ©Christopher Barr Photography. |
“If you have suppliers following their own GMPs, and they’ve already done their analysis testing, why should you have to retest the raw ingredients?” Shao questions. He believes that CoAs should be acceptable proof of purity and potency, with random testing to maintain assurances. This does not include microbiological testing, he adds. Like most supplement manufacturers, he agrees that microbiological testing, to prove raw materials are free from pathogens, should be required, with materials remaining in quarantine until test results are returned.
There is also concern that the regulations will include final product testing to validate the quantities and variety of ingredients, which could be overwhelmingly expensive, especially for multivitamins with 40 to 50 ingredients. “We are greatly concerned about that,” Seckman says. NNFA would prefer to see requirements for ingredient testing at the start of production, for verifying the quality and freshness of raw ingredients prior to processing. The group believes that this up-front testing, followed by validations that the processing environment is secure and meets requirements for effective mixing and batch production, is satisfactory for verifying the quality of the product.
“We want to make sure the manufacturers are correct, but we don’t want to unnecessarily drive up costs with duplicate testing,” Seckman says. “If you follow appropriate safeguards, that should ensure the manufacturing is performed correctly.”
The other problem with final product testing is the lack of analytical methods to evaluate many multi-ingredient finished supplements. While methods exist to evaluate the purity and potency of a raw ingredient, within many cases, it’s not currently possible to test them in combination with other ingredients in a finished product. For example, carotenoids, such as lutein, beta-carotene, and lycopene, all absorb blue light when tested using spectrophotometers. “If more than one carotenoid is in the same product, it’s difficult to isolate and validate each ingredient individually,” Shao says.
Companies also struggle to validate testing when active ingredients are mixed with inactive ingredients that can alter their properties. “You may be able to test an ingredient in one matrix, but not in another,” Reynolds says. For example, when you work with ephedra, there are methods to test its quality and potency when it’s in a pure form, but when you mix it with chocolate, it’s more difficult to evaluate.
Other potential requirements could dictate changes to facilities, added equipment and software for tracking and record keeping, and stability studies to validate label claims. “There are those company in the industry that may not have the funding to support that level of testing,” Reynolds says.
Once the FDA releases the regulations for supplements, a lot of scrambling is likely to take place. Manufacturers will need to identify the gaps between their existing processes and the new GMPs, and determine how to close those gaps in the expected time frame, which could be one to three years, depending on the size of the operation. “There will be a large education process during the implementation period,” Seckman notes.
Depending on what the new regulations say, implementation will be fairly easy for some, while it could put others out of business. “If there’s a lot of testing, people will be upset,” Shao says, pointing out, once again, that for many products, the tests don’t yet exist. “There will be a rush to develop and validate test methods, and you need a lot of equipment and research to do that.”
Reynolds expects the FDA will hold many meetings to clarify the regulations once they are published-both for the industry and for consumers-and most importantly, to define how they will oversee compliance.
“No matter what happens,” Reynolds says, “it will be a lot of work for the FDA.”