Getting QC Ready for the GMPs

Despite what the Washington Post says, the majority of supplement manufacturers take pride in their quality. But even the best quality control (QC) departments are about to be tested.

Years after the Food and Drug Administration (FDA; Rockville, MD) announced that regulations were coming, the proposed dietary supplement good manufacturing practices (GMPs) are finally about to become law. When they do, large manufacturers will have one year and small manufacturers three years to comply with a set of industrywide standards that call for installing a central QC unit, compiling batch records, and testing both incoming ingredients and final products.Some companies are ready, but most are not. Even those with good QC systems in place may not realize how much the new regulations will cost.

PRICE OF THE UNKNOWN

When FDA released the proposed GMPs, QC costs were estimated to be $47,000 for large firms and $61,000 for small firms. The cost for the entire industry was estimated to be $24 million.

FDA later admitted in public meetings that it had underestimated costs. Indeed, in comments to FDA, the Utah Natural Products Alliance (UNPA; Salt Lake City) and the Council for Responsible Nutrition (CRN; Washington, DC) pointed out how far FDA was from the true compliance cost.

“Based on consultation with analytical laboratories and other experts in the field, we estimate development of a single analytical method for a low-ingredient, nonnutrient dietary supplement to be somewhere between $50,000 and $100,000, if it can be done at all,” wrote UNPA. “This expense, when added as a cost of production, would make small-batch production economically unfeasible.”

“FDA’s assumptions are grossly inaccurate for some other variables, including the number of batches produced by large firms, number of tests per product required by the proposed rule, and percentage of required tests currently being performed,” commented CRN. “The mischaracterization of these three variables causes FDA to severely understate the industry cost of compliance with the agency’s proposed testing requirements. CRN’s estimate of testing costs is 10 times as high as FDA’s, when based on revised estimates for these three variables derived from the experience of our large member companies. CRN’s estimate for finished- product testing is $245 million, compared with FDA’s estimate of $24 million.”

Why such a vast difference? Unlike foods or pharmaceuticals, validated analytical methods do not exist for many dietary supplement ingredients (see Technology Focus, page 38). Under the new GMPs, QC departments face a difficult choice. They can develop a test method, a lengthy process that CRN estimates costs between $22,000 and $50,000 per method. Or, they can follow the extensive requirements of sections 111.35(g)(2)(i) and (g)(2)(ii) of the proposed GMPs. The regulations call for testing incoming components, dietary ingredients, or dietary supplements for any specification, as well as in-process testing to make sure the finished product matches the master batch record for identity, purity, quality, and strength.

And by the way, supplier certificates of analysis are not acceptable under the proposed regulations. QC must perform incoming raw-material testing whether or not a supplier validates purity and quality.

THE WELL-PROVISIONED LAB

Faced with new levels of testing, many companies are expanding their QC departments. Robert Rolle, senior consultant and auditor at Shuster Laboratories Inc. (Canton, MA), has some suggestions for outfitting labs to handle the workload.“High-performance liquid chromatography (HPLC), gas chromatography (GC), elemental analyses atomic absorption (AA) and inductively coupled plasma (ICP), UV and infrared spectrophotometers, and disintegration and dissolution units are among the most important instruments needed to conduct product analyses of active ingredients,” he says.

Sample-prep equipment is one area that most companies ignore. “Automated equipment for dissolution and sample preparation along with an in-house microbiology laboratory would help companies automate analyses and increase productivity,” says Rolle. “Another tool that many in-house QC labs should have is an automated laboratory information management system (LIMS) to support timely sample throughput and tracking and data generation. The high cost of this instrumentation deters some labs from purchasing it.”

AUTOMATIC MICROBIOLOGICAL TESTING AT NOW FOODS

Final-product testing and analytical methods have been the focal point of the good manufacturing practices (GMPs) discussion to date, but little has been said about microbiological testing requirements. The microbiological standards are as comprehensive-and expensive-as the product-testing requirements.When Now Foods (Bloomingdale, IL) moved to a 209,000-sq-ft facility, Jon Cassista, PhD, the company’s microbiology lab manager, was tasked with increasing the level of in-house microbial testing at a pace that could support the company’s growth. The company needed a way to quickly test raw materials, natural-food products, and dietary supplements, and at the same time perform more tests of the various sites throughout the manufacturing plant.

In 2004, Now Foods purchased a Soleris 128 multifunction rapid-test system from Centrus International Inc., a division of Eastman Chemical (Kingsport, TN). According to Cassista, it has helped streamline the company’s microbial testing program.

Essentially, the Soleris system screens raw and in-process materials and finished products or environmental samples for rapid detection of microorganisms. It features an optical monitoring instrument, ready-to-use assay vials, and advanced Windows-based software. This combination allows Cassista’s team to quickly detect and measure microbial growth with great accuracy.

“Our production efficiency costs are directly affected by how much time raw materials are held up in quarantine,” says Cassista. “The Soleris has helped us cut our quarantine time from 5–6 days down to approximately 3 days for micro testing.”

In addition, microbial tests that once required days or even weekend-long operator intervention can now be performed without supervision, eliminating costly overtime.Functionally, the Soleris system detects microbial growth by closely monitoring pH and other biochemical reactions. Color changes in the liquid-filled test files are detected by optical sensors and then recorded by a computer. The technology is sensitive enough to detect microbial growth from a single cell in the initial sample. Most results are available overnight.

Now Foods uses the system to screen for E. coli, Enterobacteriaceae, and TVC. Pretest preparation has been enhanced. In many applications, the Soleris 128 requires only a single dilution, saving the time and material costs of serial dilutions. The optical detection system eliminates the need for time-consuming colony counts, as well as manual reports.

With less time spent performing sample manipulations and processing, Cassista and his team have become more productive in their sample testing, and, perhaps more importantly, they have greatly increased the number of tests that can be conducted.

Also, Cassista and his staff moved Now Foods’ entire microbial testing operation in-house. Accordingly, Now has greatly reduced the amount of time and money required to send its samples to an independent, outside testing lab.

“When you deal with contract labs, some do not have the type of experience with nutraceuticals that our in-house lab has,” says Cassista. “It’s one thing for a chemical or analytical lab to test vitamins A or C. Looking for microbial contaminants in imported herbal components, and other exotic ingredients similar to those found in many Now products, is something else.”

Microbiological testing will also increase under the new regulations. “We expect that the work load will increase 25 to 50% in the microbiological laboratories,” says Rolle. “Every finished product will have to be tested for microorganisms. The best way for laboratories to handle this increase in work load is by using automated equipment such as bactometers and automated microplate readers.”

If capital is tight, consider outsourcing. “It makes sense to outsource when the cost of equipment and labor cannot be justified based upon the size of the laboratory or the number of samples to be tested,” says Rolle. “Companies should also consider outsourcing their product testing when a method is too difficult or involves hazardous solvents or standards.”

DEFRAYING METHODS COSTS

Recognizing that analytical methods were lacking for supplements, FDA and the National Institutes of Health’s (Bethesda, MD) Office of Dietary Supplements (ODS) cosponsored the development of these methods through a contract with AOAC International (Gaithersburg, MD).

Anita Mishra, principal scientific liaison for government and industry, says that the contract, while generous, is limited when one considers the complexities and magnitude of the task. “For example, the expert review panel (ERP) consists of individuals with credentials in dietary supplements and knowledge of specific analytes and their product matrices,” she says. “All activities related to an individual ingredient are then vetted through an ERP to review pertinent data and documents to ensure an independent, nonbiased evaluation of the guidelines, protocols, and validation data developed during the course of the study of an individual dietary supplement. Then, the Ingredient Ranking Subtask group assesses and prioritizes the dietary supplement ingredients that require analytical method development, and members of the Methods Committee on Dietary Supplements have in-depth analytical expertise to ensure methods are technically sound.”

Mishra says supplement manufacturers can participate in the process by allowing their analytical chemists to volunteer their time and laboratory resources. “It can be rewarding and cost-efficient to work together as partners toward resolution of industry and regulatory issues in a collaborative and scientifically sound manner,” she says.

Eight industry working groups have been formed to date. The groups are developing methods for dietary supplements, cranberries, omega-3s and -6s, polyphenolics, CoQ10, SAMe, herbals, and isoflavones. Collaborating companies include Now Foods (Bloomingdale, IL), Ocean Spray Cranberries Inc. (Lakeville-Middleboro, MA), MAK Wood (Grafton, WI), Cargill (Minneapolis), Applied Food Sciences LLC (Austin, TX), Compound Solutions Inc. (Escondido, CA), Pharmavite (Northridge, CA), Orchids, Phytolabs (Vestenbergsgreuth, Germany), and Novogen (North Ryde, Australia).

The benefits will be realized when methods are validated. In the meantime, quality control labs are in need of as much help as they can get. Shortterm, the GMPs will stress their capabilities. “We estimate that the burden on QC labs to meet the proposed GMPs will increase at least 25% and could actually double if raw materials and outsourced finished materials can no longer be accepted based upon a certificate of analysis,” says Shuster’s Rolle.

“The hope in the industry is that FDA will allow some level of reduced testing, such as skip lot or composite brand testing, which is allowed in the food industry,” says Rolle. “If the reduced testing is approved in the final GMPs, total costs for testing will be defrayed. But as the GMPs stand, every finished product has to be completely tested, and all test methods have to be validated.”