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Most of the world treats dietary supplements like prescription drugs. In Europe, Latin America, and Asia, dietary supplement manufacturers must prove efficacy and must meet strict standards for quality control and quality assurance. In 2003, FDA issued proposed rules that would hold dietary supplement manufacturers in the United States to a similar standard as their counterparts in Europe and elsewhere. On June 25, 2007, FDA issued the final rule to the industry for implementation.
With the issuance of 21 CFR Parts 111 and 112: Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Dietary Ingredients and Dietary Supplements, manufacturers can expect to fall under the same scrutiny as their colleagues in the pharmaceutical industry. Compliance with good manufacturing practices (GMPs) is critical for companies that want to take advantage of opportunities in the global marketplace. What’s more, some manufacturers already are following GMPs-and using the fact to differentiate themselves in a marketplace where consumer confidence is eroding over safety and quality concerns.
The chief barrier, not surprisingly, is cost. FDA estimates that compliance with the proposed rule will cost the dietary supplement industry as a whole $86 million annually and deliver annual benefits of $218 million in fewer recalls and reduced liability. The American Herbal Products Association (Silver Spring, MD) suggests that the actual benefit may be only $21 million, or even less, and the cost of compliance could be at least $700 million. In reality, it will cost money to comply, and the costs will not be insignificant, particularly for an industry built primarily on extremely low-margin products with low per-unit costs. Going forward, however, it will be the cost of coming to bat. Strategic thinking, prudent capital investments, and creative engineering and procedural improvements will be key to staying in the game.
Resources for Regulatory Information
• Current Good Manufacturing Practice for Finished Pharmaceuticals. 21 CFR Part 211.
• Current Good Manufacturing Practice in
Manufacturing, Packing, or Holding Dietary
Ingredients and Dietary Supplements; Final Rule.
21 CFR Parts 111 and 112.
• Current Good Manufacturing Practice in
Manufacturing, Packing, or Holding Human Food.
21 CFR Part 110.
• Current Good Manufacturing Practice in
Manufacturing, Packing, or Holding of Drugs;
General. 21 CFR Part 210.
• EU Directive on Food Supplements. European
• Guidelines for Vitamin and Mineral Food
• Supplements from Codex Alimentarius Committee
on Nutrition and Foods for Special Dietary Uses.
• Hazard Analysis and Critical Control Point Principles
and Application Guidelines from the FDA .
• National Advisory Committee on Microbiological
Criteria for Foods.
• Pharmaceutical cGMPs for the 21st Century-A Risk
Based Approach: Final Report Fall 2004.
CHANGES THROUGHOUT THE PRODUCT LIFE CYCLE
A narrow focus on the manufacturing facility alone would be a mistake. Compliance will require revisiting the entire product life cycle, from development through manufacture and distribution. In Europe, dietary supplement manufacturers must prove that their products are safe and efficacious, just as pharmaceutical manufacturers here and abroad must. Companies must conduct clinical trials and file with regulatory health authorities (RHAs). For manufacturers that have not gone through the process, it can be daunting, and mistakes or missteps can result in costly delays or even denials.
Pharmaceutical industry consultants can help design a clinical trial program that conforms with international regulations, guides the company through the regulatory process, and provides valuable insight into product development issues that could impact on approval.
Decisions made early in the product life cycle will drive decisions about process and facility design, including potential future compliance issues, capacity, and technology requirements.
FDA NOT LIKELY TO REINVENT THE WHEEL
Under the new rules, it appears that FDA will apply concepts that it already uses. For example, any GMP guidelines for dietary supplements are likely to be similar to those already applied to the food and pharmaceutical industries. Another, newer concept is the idea of a science-and risk-based approach to product quality regulation. Issued in 2004, “A Risk-Based Approach for the 21st Century” outlines the agency’s philosophy of applying scientific rationale and risk hierarchy when implementing programs and performing inspections. The initiative involves both FDA’s review of information submitted in applications as well as inspection of manufacturing facilities for conformance with GMPs. With limited resources, FDA will need to use this approach to determine whom to inspect and how-targeting the highest-risk sites to represent the industry and set the standards for compliance and punishment. Science-based risk management places the burden of proof on manufacturers, increasing the demands in such areas as documentation and quality assurance.
Complying with Quality Standards: Points to Consider
A consultant experienced with pharmaceutical current good manufacturing practices (CGMPs) can conduct a thorough gap assessment to identify areas for improvement. Below are a few questions that manufacturers might ask about their facilities.
Not all relate specifically to compliance, but all are part of the strategic thinking that should drive the process.
Product Development/Quality Control Lab:
• Does the lab have the instrumentation available to
meet more stringent product-testing requirements?
• Does storage for chemical materials, including
solvents and other potentially hazardous materials,
meet local and national regulations and insurance
• Are service and material access to the laboratory kept
• Are service areas clean and divorced from staff offices,
work stations, and support space?
• Are the HVAC, exhaust, fluid, and gas distribution
systems energy efficient?
• Does the lab have a system to collect bench-top dust?
• Is the exhaust air discharge system designed to
minimize fume and contaminant emissions?
• Do the facility and processes meet FDA and
international manufacturing guidelines relating to
personnel, material containment, building flows, quality
assurance, and good engineering practices?
• Do the layout, equipment operation, and safety
procedures comply with appropriate building codes,
technical statutes such as National Fire Prevention
Association (NFPA) codes, insurance underwriter
• Does the facility offer the flexibility to expand capacity
or to introduce new drug delivery forms?
Warehousing and Distribution:
• Does the materials management system provide
GMP-level storage for materials?
• Is the materials management system as accurate and
efficient as possible?
• Does the materials management system allow the
flexibility to change form of receipt and shipping
should shipping modes or customer preferences change?
• Does the materials management system offer
sufficient visibility into all warehouse activities?
Another concept likely to come into play is hazard analysis and critical control points (HACCP), a management system that currently addresses food safety through analysis and control of biological, chemical, and physical hazards from raw material production, procurement, and handling through manufacturing, distribution, and consumption of the finished product. The seven principles of HACCP are:
1. Conduct a hazard analysis.
2. Determine the critical control points.
3. Establish critical limits.
4. Establish monitoring procedures.
5. Establish corrective actions.
6. Establish verification procedures.
7. Establish record-keeping and documentation procedures.
Successful implementation of an HACCP plan requires a firm commitment to the concept by top management. It is also FDA’s position that current GMPs are an essential foundation.
FINDING THE STARTING POINT
For most companies, the first order of business will be a gap analysis to assess how and where they might be putting themselves at risk. A thorough analysis should look at facilities, personnel training, process documentation, warehousing, and quality programs; identify those areas that have the most impact; and set priorities. Where does the facility vary from international regulatory nutraceutical statutes or from FDA statutes? What are the shortcomings of its utility systems?
What improvements can be made in flow of personnel, materials, and waste handling? Is the manufacturing technology current or could it be more efficient? The analysis should address engineering issues, such as program and process identification; critical utilities systems, such as heating/ventilation/air conditioning (HVAC) and purified water; energy efficiency; and commissioning and compliance. It should also address environmental health and safety issues and regulations. Rest assured that the findings don’t always require a new building. In some cases, the changes may be as simple as increasing the quality staff and ensuring that personnel are wearing the proper protective garb, adjusting the cleaning process, or changing the flow of materials through the building. In others, changes to the facility or equipment may be necessary.
For example, one area of significant concern is cross contamination between products. Determining how far to go to minimize the risk will depend on a number of factors-chief among them being the nature of the ingredients in question. If an ingredient is a potential allergen, it will require a higher degree of risk management than a product or ingredient that is unlikely to cause an adverse reaction. One company may be able to reach an acceptable level of risk by changing procedures-for example, by ensuring that one team is not running production equipment in two different rooms, or by setting up gown-changing areas in between two production areas. Another company may need to make changes in its HVAC system, which is perhaps the single weakest area in most facilities. Although upgrading or replacing an HVAC system can be a large expense, choosing an energy-efficient design might result in operational savings that can help offset the costs-as well as demonstrate a commitment to the environmental values that many of the company’s customers share.
Five Things You Need to Know about the GMPs
By Michael Tousey and Carol Brennon
1. If it isn’t written down, it didn’t happen.
There’s an old saying in many regulatory and quality departments: “If it isn’t written down, it didn’t happen.” That is because during an FDA inspection, companies must be able to demonstrate GMP compliance. One of the most critical ways this is accomplished is by providing written proof that your company actually does what the regulations and your procedures say. Make sure all cleaning, training, and procedural activities are documented properly.
2. Many pest-control programs are inadequate.
Your company has a pest-control program-but will
it stand up to scrutiny? This is one of the areas many
companies receive an inspection observation for, and the reason is that their programs are inadequate. A comprehensive pest-control program carried out by a qualified pest-control company, documented completely and accurately, is the way to go. This is not an area to try to save money by delegating it to the company janitor or hiring a nonprofessional company. Get your pest control program in good order.
3. Your employees must be trained and qualified.
GMPs require that all employees be trained and qualified to perform their duties. So, how will your employees stack up when their training records are examined during an FDA inspection? Your employees must be trained for each task they perform. Who trains them? Who qualifies that the training was effective and the employees are now trained and ready to perform their duties? How is the trainer qualified? Yes, these are all questions you may be asked during an inspection. Be ready to answer them and provide procedures for how these activities are performed and documented. Don’t stop there! Focus on the quality of your employees, too. Build pride into your process and allow the operators to grow along with quality and productivity.
4. Written procedures should match what your employees
and processes do.
For many companies, it would be easy to make the statement that if they only did what was written in the standard operating procedures (SOPs), the process would not be successful. How many times do your operators say their SOPs don’t work? Once is too many! Procedures must match what is being done or there is a problem, not just from the FDA investigator’s perspective, but because your company is not functioning optimally. Your procedures and processes must accurately reflect actual practices, while adhering to regulatory requirements.
5. Audits are not just for accountants and the IRS.
If there is one message to deliver, it is that we
are all part of the quality team, all of the time. Did you know that FDA requires companies to conduct self audits? It is important that your company has an internal audit program to determine your compliance to regulatory requirements, as well as adherence to your own company specifications and procedures. This does not mean you must create a new department in your company, though. You may use the service of an auditing company-just make sure that you have carefully created your audit policies that state the expectations of your audit program.
With the requirements of the new dietary supplement GMP ruling, companies are being motivated to take action now. The first step is to complete a GAP assessment audit. A GAP assessment determines where your company is now and where it needs to be. Step two is to create and execute a plan for compliance. The final step is being active and prepared for an FDA inspection. You do not have to do this by yourself with your own staff; you can hire outside help.
In reality, very few dietary supplement manufacturers are dealing with products that require the level of risk management that pharmaceutical companies provide for potent compounds, and so they are unlikely to require high-containment strategies. But products are at risk any time they are exposed to air-where tablets are made and before they are bottled or packaged. It can pay to look at those facilities and processes and take action to minimize risk, such as reducing the number of steps in the production process or changing the procedure for transferring materials. Adjusting the production schedule to make fewer batches can reduce the number of cleanings and, therefore, lower the potential for contamination. Bear in mind, however, that it will be necessary to document the rationale for these procedures. The regulatory bodies, specifically FDA, need to understand the product and process in order to evaluate any potential risk to the public.
Whether the issue is cross contamination or product consistency, the challenge remains the same: to balance procedural and engineering changes in order to manage risk effectively-and cost effectively. The Achilles’ heel of procedurally based risk management is that the program is only as good as the people who implement it. A proven engineering solution is always safer. For example, an automated production process is more repeatable than manual batch mixing. Companies that utilize procedural controls will need to be able to provide proof to the RHAs that the procedural controls are effective. Depending on people to be the control always increases risk, and in some cases it is wise to spend money on “people-proof” solutions. If engineering controls are not financially feasible, additional training, signage, and other means may help reinforce the procedural controls. Risk management always comes at a cost, and each company must decide for itself what level of risk it can afford to take.
EXAMINATION ADDS VALUE
As noted above, it does not necessarily require a new facility to meet the international standards of the newly enacted FDA regulations. This is another area for strategic consideration, based on products produced, quantities, and plans for growth, to name a few factors. In some cases, leasing or purchasing another facility might make sense. In other cases, a renovation is the better choice. Large-scale renovations can be phased to spread out the capital requirements. Outsourcing production is yet another option.
Regardless of whether a company builds a new facility from the ground up or works with an existing site, the exercise of moving toward compliance can have benefits that extend beyond the peace of mind that comes from knowing that an FDA warning letter is unlikely. Greater energy efficiency, as noted above, is one possible outcome. A look at production systems might reveal areas that could benefit from debottlenecking solutions. Perhaps warehousing and distribution activities can be streamlined. Statistical process control systems can enhance product consistency and provide a foundation for continual quality improvement. Automation can reduce the likelihood of errors in production or distribution. Automated systems can also support greater efficiency and may allow manufacturers to allocate human resources more efficiently. Information technology solutions exist that can minimize the paperwork burden required for documentation. In most cases, enhancements required for compliance will increase the product’s cost per unit, but finding ways to do things more efficiently with fewer opportunities for error can often help balance those costs.
The potential benefits do not minimize the challenge that dietary supplement manufacturers face. A higher level of regulation will clearly make an impact on most companies in the industry. Some will weather the change successfully and others will not, but it is an inevitability that must be addressed. The number of FDA warning letters issued to the dietary supplement manufacturers since 2000 suggests that the industry is already on the agency’s radar. Meeting the challenge successfully requires a strategic plan that achieves compliance and provides an acceptable level of risk management within time and capital constraints. A consultant with experience in pharmaceutical-level GMPs can help guide the integrated project development process and provide creative solutions to attain those goals. The result can be products and processes that comply with national and international regulations, minimize safety concerns, and deliver value-added benefits such as operational cost savings and increased consumer confidence.
GMPs for Ingredient Suppliers: A Q&A with Bergstrom Nutrition
Even though FDA intended the good manufacturing practices (GMPs) to apply to dietary supplement manufacturers, some dietary supplement ingredient suppliers are also seeking GMP certification. Bergstrom Nutrition (Vancouver, WA) earned certification through the Natural Products Association (Washington, DC) in 2000 and passed recertification audits in 2003 and 2006. Nutritional Outlook talked with Bergstrom Nutrition technical director Tom Freeman and director of quality control Rod Benjamin about some of the reasons why ingredient suppliers may be interested in GMP certification.
Why are ingredient suppliers like Bergstrom making the extra effort to become certified?
Tom Freeman: “It has always been the philosophy of Bergstrom Nutrition to provide the highest-quality MSM available. Even though as a raw material ingredient supplier, Bergstrom is not required to comply with the GMPs, the requirements provide a very good operations framework for manufacturing a high-quality product. All parts of the manufacturing, holding, and distribution process are closely monitored. Additionally, the GMP certification provides an independent, third-party assurance that our MSM is of the highest quality. Any dietary supplement manufacturer that really cares about the quality of its products should be demanding about the quality of its ingredients.”
Is the certification process for ingredient suppliers different from the one for manufacturers?
Tom Freeman: “Currently, there are a number of certifying bodies for dietary supplements, among them, NPA, NSF, and USP. FDA has no plans to provide certification for its GMP regulations, so certification must be done by one of the third-party certification bodies. Before the promulgation of the new GMPs, there was no distinction between raw material ingredient suppliers and dietary supplement manufacturers as far as the requirements, desirability, or benefits of GMP certification. These certification programs have essentially treated suppliers and manufacturers the same. This may change as the certificating bodies modify their certification programs to incorporate FDA’s GMPs into their own GMP certification requirements.”
Can a supplier or manufacturer still be GMP-certified if it doesn’t test its materials on site?
Tom Freeman: “The new regulations do not specify that testing must be done on site. The GMPs require that specifications must be set for any dietary supplement component, which includes raw materials. Incoming raw materials must be shown to comply with the specifications by either ‘appropriate tests or examinations’ or by relying on the certificate of analysis from the supplier. The regulation does not specify who does the test or where the test must be conducted.”
How likely are manufacturers to petition for exemption to 100% identity testing?
Tom Freeman: “It is unclear right now how many manufacturers are planning to file a petition for exemption with FDA. Many of the larger manufacturers have an in-house lab and established procedures so that the required identity won’t represent too much of an additional analytical burden. Many mid-sized and smaller manufacturers that rely on third-party testing probably will be very likely to evaluate the benefit of petitioning for exemption. The complexity of the petition will depend on many factors, including the type of ingredient and the number of ingredients supplied by the particular supplier. Bergstrom Nutrition is a single-ingredient supplier with a consistent, high-quality product that should help simplify the petition process.”
How important is the development of validated analytical methods when it comes to testing and GMP compliance? Given the lack of validated methods overall, how can suppliers and manufacturers be sure that they are testing ingredients correctly?
Rod Benjamin: “The importance of validated analytical methods is paramount to both the compliance and enforcement of the published GMPs. Identity, purity, strength, and composition are the backbone of the final rule. Without validated analytical methods, what defines these key things can differ from one interested party to the next. These differing opinions may be able to show reasonable substantiation for each of the differing methodologies, and it could come down to one company arguing with another. This could ultimately get very messy, even leading to possible litigation.
“Validation is the process of demonstrating or confirming the performance characteristics of an analytical method. These performance characteristics are things like specificity, matrix applicability, and degree of reliability. All analytical methods need to have some level of validation. Due to the lack of compendial methods for many of the materials in our industry, many methods are single-lab validated (SLV). SLV is still much better than no validation at all. SLV done properly ensures proper evaluation of a method’s performance characteristics. SLV training classes are available through many industry groups, including AOAC.
“Bergstrom Nutrition has been working with AOAC since 2005 on developing official methods for analyzing MSM. The SLV for GC assay of MSM and low-level determination of DMSO has been completed by Joseph Zhou of Now Foods (Bloomingdale, IL). Bergstrom Nutrition believes that it is important for companies within our industry to commit resources toward helping develop and validating methods.”
How valuable and useful are certificates of analysis in light of the new GMP requirements?
Tom Freeman: “Certificates of analysis have taken on a new value now that FDA’s GMPs allow a manufacturer to rely on a certificate of analysis in place of ‘appropriate tests or examinations,’ provided that a number of criteria are met. The manufacturer must qualify the supplier by establishing the reliability of the supplier ’s certificate of analysis, document the qualification, and periodically requalify the supplier. Additionally, the certificate of analysis must include the test methods used, the limits of the test, and the results of the test.
“Reliance on the certificate of analysis can greatly reduce the cost of analytical tests, especially for companies that rely on third-party testing. Qualification of a supplier’s certificate of analysis will most likely entail an audit of their facility and an analysis of the supplier’s historical analytical results. A single-ingredient supplier with a long history of exceptional analytical results, like Bergstrom Nutrition, should make qualification of the certificate of analysis fairly easy. In order to rely on the certificate of analysis, it is important for the manufacturer to ensure that ingredients come from reliable suppliers.”
Identifying Raw Ingredients
Amajor theme of the new good manufacturing practices (GMPs) for dietary supplements is that manufacturers are responsible for verifying the identity of their incoming raw ingredients. However, another im portant goal of the GMPs is the avoidance of adulterants and other contaminating materials.
Buchi Corp. (New Castle, DE) recently unveiled a new analytical system that may help automate both of these tasks. The Nirflex N500 quick ly verifies the identity, purity, and quality of ingredients. Although the system accommodates exhaustive batch testing, it also offers a zero-sample option, enabling operators to scan bulk powders directly through plastic bags or glass vials.
“The risks associated with putting an ingredient with undisclosed or unwanted adulterants into the marketplace can be significantly diminished by this simple method that checks raw material as it is received and again as it is shipped out,” explains Buchi’s Cynthia Kradjel. “The Fourier transform near-infrared method by Buchi, once set up, can be operated by receiving personnel in the warehouse who probe the drum with a fiber-optic wand and receive a pass or fail on the spot. If the ingredient is subpar, the manufacturer is immediately alerted to the problem and can take appropriate action without affecting the integrity of its production processes.”