Eliminating the Rotten Apple
There are some industries where GMPs are not mandated, such as those where the consequences of having a sub-standard product are immediate and obvious. The dietary supplement GMPs (21 CFR, Part 111) are substantially different from the food GMPs (21 CFR, Part 110), which did not mandate quality except in terms of hazard—consumers can taste a rotten apple. For the most part, the very nature of dietary supplements, based on the promise of health and promotion of wellness, makes it difficult for consumers to ascertain quality, outside of exceptional contamination resulting in adverse events. Hence, the desired outcome of the new regulations is to ensure industry is purchasing unadulterated ingredients from a known source with the required functional activity for their intended use.
Establishment and implementation of sound GMP regulations largely eliminate the need for regulators to perform off-the shelf “gotcha” testing of finished products. Given the enormous number of finished products on the market and the diversity of distribution routes (e.g., web, MLM, retail), a post-market surveillance system based on random testing would not stand much of a chance of catching subpar products in a timely fashion. Instead, FDA would spend its time and resources chasing the adverse events caused by these “rotten apples.”This is both inefficient and damaging to the industry’s reputation. A mature GMP program shifts the burden away from FDA in a way that allows the industry to utilize its expertise to set and maintain quality standards.
From McIntosh to Apple Sauce
Arguably, the GMP measure that has caused the greatest consternation, or perhaps anxiety, among industry members is the 100% identity testing requirement. Largely driven by FDA’s experience in the plantain/digitalis case, the agency determined the public health risk associated with misidentification of dietary ingredients is significant enough to require a higher degree of quality assurance. The GMPs also require evidence that laboratory examinations and testing methodologies are appropriate for their intended use (21 CFR 111.320(a)) and that methods used to determine specifications are appropriate and scientifically valid (21 CFR 111.75 (h)(1)). Already from the handful of Establishment Inspection Reports (EIR), available on theagency’s website (http://www.fda.gov/ AboutFDA/CentersOffices/ORA/ORAElectronicReadingRoom/default.htm), it can be seen that analytical methodology, specifically the use of methods not fit for purpose and/or not demonstrated to be scientifically valid, is a notable challenge. The farther your ingredient is from the field, the more challenging the task of demonstrating identity becomes, as fewer analytical approaches are available for processed materials. Given that identity testing is infinitely more reliable when conducted on whole materials when compared to highly processed materials, you could find that your ingredient buyer, not QA manager, is the key to facilitating GMP compliance.
In the past, some manufacturers have taken a black box approach to raw materials. They would receive a 55 gallon drum (or freight car) full of an amorphous brownish powder, accepted the information on the certificate of analysis at face value, and dumped it into their mixer—all without a hint of curiosity or further testing. What should have they been looking for and what will they now be required to know? Well for starters, the plant species and plant part must be known. This could be followed by the when, where and by whom of cultivation, collection and harvest; processing conditions and details concerning standardization, if applicable; and of course the entire evaluation process. Even outside the botanical arena there are challenges, such as identifying whether a single entity ingredient is natural or synthetic, isomerically pure or a racemate, and so forth. All of this information, which the manufacturer must know, cannot be ascertained by visually inspecting the brownish powder and its associated piece of paper. Hence, if there is no suitable test to verify the information, you need to know the material pedigree—supply chain management is the key.
The basic reason why it is not preferential to rely on testing of incoming materials to assure quality is not technical, but rather based in sound business practice. If you perform a test and get a result that disqualifies the material, you have to reject it and send it back. This is a hassle at the best of times, but if you are trying to maintain a “just-in-time” processing facility, having to shut down production line is sure to ruin your day. Knowing more about your supplier from the start will mitigate certain risks and might help you save money.
The technical reasons for avoiding a situation where you are reliant on testing for quality parameters in an unknown commodity are based in the nature of analytical methods, where the scope and applicability of the method defines the possible outcome. Without key knowledge of the supplier, there is simply no way to anticipate what testing may be important. For example, those manufacturing male enhancement products may be assiduously testing for sildenafil and other such substances, but the unknown risk factor may actually lie in the geographic location of the raw material producer—say an earthquake-prone city and proximity of their strychnine-containing rat poison in an open container on a rickety shelf above the open hopper in which the raw materials are mixed. Under most circumstances, there would be no reason to suspect (or test for) strychnine (or floor cleaner or paint-thinner) in your product, so including such a test in your specifications would be unlikely. In this situation your first hint of trouble might be the visit from the adverse events response team.
How You Like Them Apples?
You cannot test for all possible adulterants and you cannot test quality into an ingredient. So control of your raw material supply is vital. The explosion in the marketplace caused by DSHEA, along with the globalization of supply chains, has resulted in an increased need for supply chain control accompanied by a diminished capacity to manage the supply chain effectively; resources, both financial and human, are limiting factors. The result is an attempt to backfill for the lack of supply-chain control by attempting to test quality in, rather than to acquire quality in the first place. Testing has become important because the supply-chain is perceived to be unmanageable. The problem is compounded with suppliers of dietary ingredients and other dietary supplement components (such as excipients) being subject only to the less stringent food GMPs (Part 110). FDA has clearly placed the responsibility on manufacturers to ensure their raw materials are properly sourced and qualified.Manufacturers can no longer accept at face value the information provided on a supplier’s Certificate of Analysis.
FDA has consistently repeated to industry, “know your supplier” since the publication of the dietary supplement GMP Final Rule in 2007.This is a clear message that FDA considers ingredient supplier qualification by manufacturers and manufacturers’ records on supplier qualification a primary target for GMP inspections. For more information on FDA’s expectation of the types of information that should be collected when a supplier is “qualified,” catch Bill Frankos’s presentation “Qualifying Dietary Supplement Ingredient Suppliers: FDA’s Perspective” scheduled during the SupplySide West Trade Show (http://www.supplysideshow.com/west/2009/nutrition_track1.html).
One Rotten Apple Spoils the Whole Barrel
The bottom line is that the quality of a dietary supplement is only as good as its components; an inadequate or absent supplier qualification program can be devastating. Industry is grappling with the “how” of getting to know their suppliers.The current state of practice for qualifying suppliers and ingredients is reliant on issuing questionnaires; an approach fraught with large error margins and potential liability.There must also be a pass/fail component, as presumably not every supplier or ingredient will qualify. On-site or third-party supplier audits have been presented as a solution; however this requires significant resources and third-party audits do not necessarily provide the needed information to make a decision.
The answer truly lies somewhere in the middle. The need for an on-site or third-party must be placed within the context of your business strategy. For example, if your business is dependent on an off-shore supply from a politically unstable area, it is probably worth the effort to visit them in person. The key to a supply chain management program is to include both business and quality/consumer safety considerations and risks. The character of your business-to-business interactions with suppliers is as big an indicator of their quality management program as it is proof of a third party audit.
Millions Saw the Apple Fall, But Newton Was the One Who Asked Why
All manufacturers, regardless of the industry sector, must develop a Supplier Quality Assurance (SQA) program that identifies all the potential “bad apples.” This is a key business tool. The first step to an SQA program is to perform a risk assessment for each ingredient, which allows a company to prioritize the development and implementation of the SQA Program. A risk assessment does not need to start out as a complicated process—one can begin with a simple quantitative risk assessment.
A risk matrix can be used as a means to comply with GMPs in the same way Hazard Analysis Critical Control Point (HACCP) plans serve this purpose for food. HACCP plans require identification of all biological, chemical or physical hazards that may be associated with each input. Examples of incoming food hazard statements include “pathogen contamination because of poor animal husbandry practices” or “mycotoxin contamination because of improper harvesting and storage conditions.” The probability that the hazard will occur and the consequence of occurrence constitute a risk assessment. While dietary supplement GMPs do not use the term “HACCP” specifically, HACCP concepts are present throughout the regulations.
Each manufacturer should conduct a risk assessment for each dietary ingredient. The risk assessment must reflect an understanding of where the true risks lie within the supply chain. What risks are inherent in the dietary ingredient itself; which are introduced by geographic location; is product adulteration a risk; what impact does the political environment have? The risk assessment element can evolve over time to a more qualitative format and should ultimately reflect your business needs and guide resource allocation. This is particularly important for businesses that typically purchase scores of dietary ingredients. The SQA program can be developed further, once the risk assessment is completed, to include other criteria such as product cost, volumes, service and delivery. These can be part of a decision matrix that guides a company to determine how much supplier control is necessary.
Once a company has developed its SQA Program and determined how resources should be allocated there are many external resources available to assist in the implementation of your program. For example, the American Herbal Products Association, Consumer Products Healthcare Association, Council for Responsible Nutrition and Natural Products Association, have developed the Standardized Information on Dietary Ingredients or “SIDI” protocol.SIDI facilitates information exchange by guiding the manufacturer to identify the required information for qualification of their ingredients. From a supplier perspective, SIDI also provides the functional advantage of putting all ingredient information into one standardized format.While vendor questionnaires alone are inadequate, the information provided through SIDI will contribute to streamlining one aspect of your SQA Program. I encourage those seeking more information on SIDI to visit www.crnusa.info/SIDI/.The members of the Joint SIDI Working Group, led by the four trade groups, are considering development of more useful tools such as guidelines to standardize ingredient CofAs, for how manufacturers should verify suppliers’ CofAs and for GMPs specific to dietary ingredients.
A Stone from the Hand of a Friend is an Apple
Since the passing of DSHEA the industry has pushed FDA to promulgate dietary supplement-specific GMPs, in recognition that these standards have the potential to make industry stronger and to give consumers more confidence in the quality of these products.Ingredient supplier qualification is now required for compliance and is critical for business success.