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GMP compliance: ready for stage 2?

Erik L Goldman is New York-based editor of Holistic Primary Care, which provides health-care professionals with scientifically sound information on natural medicine and holistic health care.

With new Good Manufacturing Practices (GMP) regulations set to kick in for midsize manufacturers at the end of June, third-party analytical testing labs are gearing up for what will no doubt be a surge in business, and supplements executives are scrambling to fatten up their quality-contol (QC) budgets.

But the GMPs, which require finished-product companies to verify the identity of all ingredients in their formulas through scientifically valid methods, beg an important question: does the industry have the analytical methods needed to support this widespread QC effort?

The fact is that for a lot of ingredients, there are no published, third-party validated methods. This is particularly problematic for botanical ingredients. Method validation for herbs lags that for vitamins, minerals and other common nutrients for which monographed standards were established years ago by the AOAC, US Pharmacopeia or other independent entities.

"Method validation is going to be a big issue going forward. We're lacking in adequate numbers of validated methods for analyzing a lot of herbs," says Mark Blumenthal, founder and director of the American Botanical Council. He told Functional Ingredients that while the new GMPs call for the use of "scientifically valid methods," they don't call for third-party verification and validation of the methods being used. "That's very, very different.

"Method validation is a big part of the whole GMP quality-control endeavour, but it can cost up to $50,000 to develop a well-validated analytical method, so establishing methods for all the commonly used medicinal herbs is an expensive undertaking," Blumenthal says.

It's a project the Office of Dietary Supplements at the National Institutes of Health is taking on, but it will take a lot of time and money. And it won't be finished any time soon.

The botanical answer
Elan Sudberg, lab manager for Alkemists Pharmaceuticals, a Costa Mesa, California-based analytical testing lab, estimates that there are third-party-validated ID methods for fewer than 10 per cent of all botanical ingredients in common use. What are analytical chemists and QC officers supposed to do with the other 90 per cent?

Adapt, that's what.

Sudberg says that he and others routinely adapt methods developed for one type of plant product in the identification of other, similar plant products. For example, if you've got raw material derived from a particular root or rhizome for which there is no AOAC- or American Herbal Products Association-validated method, Sudberg says he might adapt the methodology used for other similar root products.

"We give full method disclosure, and specify exactly what we did and how we did it. It needs to be accurate and reproducible. Someone else should be able to follow that same method, and hopefully, arrive at the same conclusion."

Botanicals are bugbears for analytical chemists simply because of their inherent complexity. Within a given species of plant, there can be hundreds of biologically active components, the concentrations of which vary with climate, plant part, growing conditions and handling. And that's assuming a particular sample is pure and uncut. Sudberg says that, unfortunately, it is not uncommon for raw-materials suppliers to pad their plant powders with all manner of fillers, including maltodextrin, rice powder, even sand.

Letter vitamins and minerals, on the other hand, are about as simple as it gets. And because they're cheap to produce, there's little risk that raw materials have been 'extended.'

The FDA's position
According to Richard Conant, director of quality assurance services at AIBMR, the FDA recognizes the fact that method validation is lacking for many common ingredients. Regulators are not expecting the industry to pull rabbits from hats.

Regulators are not expecting the industry to pull rabbits from hats
"The FDA has made it clear that they're only expecting us to use existing methods. If there's no validated method, they don't expect manufacturers to start inventing things." He reiterates that third-party validation of any test to the point where it is published as an 'officially recognized' method is a long, arduous and costly process.

In his estimation, the industry has everything it needs as far as analytical methods for simple things such as vitamins, minerals and essential fatty acids. But it's got a long way to go for speciality ingredients like glucosamine, chondroitin, coenzyme Q10 and dozens of others.

Probiotics are another area of concern. Beyond simple identification of probiotic strains, the analytics for product quality are full of holes. "We don't really know how to measure viability in the gut. We can measure bacterial counts at manufacture, but we don't know the curves for potency. The shelf lives and viability of different organisms vary quite a lot," Conant says.

One thing is clear: GMP compliance will increase the cost of production, and it will disproportionately affect smaller companies that produce smaller volumes.

"You have to do the identity testing on every batch, every time. So this is really going to hurt smaller companies. Unfortunately, there's no way around that," says Sudberg. "If you can increase batch size you can save money."

AIBMR's Conant agrees. "If you're doing high-volume production, using hundreds of thousands of kilograms of raw materials, the analytical testing won't be as onerous. Bigger manufacturers clearly have the advantage."

Both experts say they expect manufacturers to pass these costs on to customers, though the degree to which consumers will tolerate increased prices in a down economy remains to be seen.

Conant says he expects GMP compliance to have a cooling effect on multi-ingredient 'kitchen sink' formulations. If it costs $200 to $250 per ingredient just to do high-performance liquid chromatography for ingredient identification, the cost is obviously going to be higher for a product that contains 30 ingredients, compared to a simpler formula. This might not be a bad thing in the long run, as it will cut down on 'me-too' formulations in which manufacturers throw in inconsequential amounts of 'hot new ingredients' just so they can boast that their products include them.

What's in your toolbox?
When it comes to things like multivitamins, manufacturers will have to validate the identity of each component ingredient, but fortunately for the QC budget, they won't have to test for quantity of all components in the final product. "You'll be able to pick one or two, and test the final product for these. But for everything else, you'll be able to rely on 'testing by input,'" says Conant. This means simply going back to the manufacturing logs and demonstrating that the correct amounts of all raw materials, as determined by the master formula, were put into the batch.

Sudberg is a strong advocate of 'fit-for-purpose' thinking, when it comes to applying analytical methods. This means using the right tool for the right job, and "not using a sledgehammer to drive a nail into the wall."

For many botanicals, microscopy plus high-performance thin layer chromatography is sufficient to guarantee ingredient identity. These methods are well established and inexpensive. There's seldom the need to go into genetic testing or other advanced and more costly testing methods.

He also cautions against use of Fourier Transform Infrared (FT-IR) or other IR-based methods for botanicals. These techniques are popular because, while the machines are expensive, they're very easy to use and can be run by lay people with no chemistry training. Much like a StarTrek 'Tricoder,' you simply stick a probe into a sample, and it tells you whether that sample is or is not the substance in question.

FT-IR works really well for single-component ingredients such as letter vitamins. But it stumbles when applied to inherently complex things such as herbs. Companies that spend on FT-IR for botanicals are probably not getting their money's worth.

Sudberg says the GMP requirements will end a long period of 'willful neglect' in the supplements industry. "For a long time, a lot of companies have sort of appealed to ignorance. They put their trust in certificates of analysis provided by raw-materials suppliers, and don't go any further. That's pretty questionable, and under the new regs, that won't hold up."

Conant says GMP compliance should not be overly burdensome to companies that already have long-standing commitments to quality. "A lot of what is required is stuff you should be doing anyway."

The really big question mark is around the FDA itself. "Over time, we'll see how the FDA enforces the GMPs. We'll see what they make big issues over, and what will provoke them to take action," Conant says.

GMPs: mandate for product quality

By Irfan Qureshi, John R Endres, Alexander G Schauss

The next critical date for the dietary-supplements industry to comply with the final rule in Good Manufacturing Practices (GMP) is fast approaching. Starting on June 25, 2009, medium-size companies — those with 20 to 499 full-time equivalent employees — are subject to GMP inspection by the Food and Drug Administration.

Many firms in this category outsource the manufacturing, packaging, labelling and warehousing of their finished dietary supplements. GMP requirements apply to each of these operations. The firm whose name appears on the label (referred to by terms such as 'own-label distributor' or 'label holder') bears full responsibility for ensuring that every SKU in its product line meets GMP standards and is accountable to the FDA for any failures.

The GMP rule is more than just a set of standards for the manu—facturing facility. Certainly much of the rule deals with manufacturing operations, covering key areas such as plant design and cleanliness, equipment calibration and sanitation, process controls, laboratory operations, employee training, and personnel hygiene practices. The big picture is that GMP presents the industry with a regulatory mandate for product quality.

GMP compliance and quality assurance are inseparable. A robust programme for complying with the GMP rule is tantamount to a Quality Assurance Master Plan. It begins at the product-development stage and includes all steps needed to deliver a dietary supplement that has the identity, purity, strength and composition represented on its label. Written specifications must be established for the finished product and for the process controls that ensure every lot meets those specifications. Specifications are quality standards.

The own-label distributor must cross two major hurdles: all operations — in-house and out-sourced — must comply, and the firm must have the documentation to verify it. A fundamental rule of Good Manufacturing Practices is that activities not recorded never happened. Record keeping is an essential element of GMPs. With June 25 right around the corner, the time is now to make sure GMP-compliant processes and procedures are in place at every operational level in the production of dietary supplements.

GMP consulting companies are unanimous that many small to medium sized companies are overwhelmed by the process for GMP certification. For more on this topic, please see part 2 of this article.

Irfan Qureshi, ND, is vice president of technical and regulatory affairs at AIBMR Life Sciences. John R Endres, ND, is chief scientific officer. Alexander G Schauss, PhD, is president and CEO of AIBMR, which offers worldwide consulting services in GMP compliance and other technical matters, with 25 years of experience.

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