Despite the US FDA's recent issue on cGMP for supplements, Philip Payne, business development manager at RSSL, argues that the wider sourcing of ingredients sets the industry many challenges in terms of contaminants and counterfeiting
After 13 years of negotiations and consultation, the US FDA has recently released an 800 plus page document detailing its Final Rule on the Current Good Manufacturing Practice (CGMP) standards expected of dietary supplement manufacturers. Interestingly, the publication of the standard comes at a time when several commentators in the US have cited serious and fatal contamination incidents involving pet food as an indication that a dietary supplements disaster is a problem waiting to happen. It also comes at a time when regulators in Europe have reported a massive increase in the seizure of counterfeit pharmaceutical and healthcare products. In both cases, the booming production capacity and export potential of relatively unregulated new economies are cited as being a key component of these two different, but related, problems.
The pet food issue involved a wide variety of pet foods and animal feeds containing contaminated vegetable proteins imported into the US from China. Reports suggest that thousands of cats and dogs have died as a result of kidney failure caused by this contamination, and there have been major recalls of pet food in many countries as a consequence. Whilst other possible contaminants have been proposed, the FDA has focused its attention on melamine, a chemical most often used in plastics and resins. US journalists claim that Chinese factory owners have admitted using melamine to boost the nitrogen content of vegetable proteins in an attempt to boost the apparent protein content. China explicitly banned this practice only in April this year, but has denied any connection to the pet food scandal.
As it happens, during the same period, the FDA was forced to issue warnings to the healthcare industry world-wide that supplies of glycerin should be checked for contamination with the poisonous anti-freeze, diethylene glycol. This came after the FDA became aware that contaminated dental products had been found in several countries. Once again, the finding led to a number of seizures and recalls in different countries.
Counterfeiting and contamination may appear to be different issues, but in truth, when done on a bulk scale, contamination of ingredients is essentially the same crime as counterfeiting. False supplies are being passed off as genuine, either by having their appearance or chemical profile 'improved', or simply by being substituted with cheaper, inferior and possibly dangerous, ingredients. The five-fold increase in seizure of counterfeit pharmaceutical products in Europe should be seen at least as an indication that there are plenty of manufacturers and distributors happy to trade in illegal goods, and no industry is any more or less vulnerable than any other. The rogue trader is only concerned to seek out the opportunities for maximum reward with minimal responsibility, and will seek out that opportunity with whatever product is available. Within the pharmaceutical industry in particular, more emphasis is being placed on Good Distribution Practice (GDP) to reduce the likelihood of counterfeiting.
Whilst not directly concerned with nutraceutical products both the above stories highlight the need for manufacturers of these products to be vigilant about quality issues, particularly in respect of the supply of raw ingredients. Many ingredients used in the production of nutraceuticals are sourced from countries where there is limited regulation and serious difficulty in establishing the credability of suppliers. Writing in Functional Foods and Nutraceuticals in June 2007, in the wake of the pet food scandal, Todd Runestad claims that the industry has long known about issues with spiked botanicals. He goes on to quote Loren Israelsen, president of LDI Group consultancy in Utah as saying, 'Why does our industry tolerate spiking of important botanical extracts wherever they come from? We know this is going on. The reason, as always, is that it is profitable. Too many in the supply chain turn a blind eye for the sake of a few nickels per kilo. This is not a 'China' problem. This is a self-regulation problem.'
Among other things, self regulation requires reputable manufacturers to take measures to verify the authenticity, purity and quality of their supplies through appropriate analysis. As the new Final Rule observes "..quality begins with the starting material and continues with the product being manufactured in a reproducible manner according to established specifications. It is not sufficient, nor effective, to rely solely on end product testing to assure the quality of the individual dietary supplement product sold to the consumer". Citing an example of a dietary supplement that had been contaminated with Digitalis lanata (foxglove) the Final Rule is unequivocal that had there been a system in place "to perform identity testing upon receipt, the manufacturer could have prevented the adulterated product from entering the market place".
The problem is that providing such a system is easier said than done. Published and validated methods are not available for testing the quality of every conceivable ingredient, or for identifying every conceivable contaminant. That said, at RSSL, the Natural Products Laboratory provides a contaminant screening service, which can highlight problems, even if the contaminant is not specifically identified by the screen. The same laboratory works on methods of ingredient authenticity, though it has to be acknowledged that proving the authenticity of an ingredient, particularly once it has already undergone some processing, is a significant challenge. In this respect, the supplement/nutraceutical market is no different from the conventional food ingredient market, for many food ingredients are sold ground, powdered, pressed, pulped and otherwise processed. However, the lack of published methods cannot be taken as an excuse for doing nothing.
With a little commitment and effort it is possible to develop methods for screening, identifying and assessing the stability of natural products based on analysis of key chemical constituents. The chemicals chosen will depend on the ingredient concerned. RSSL has developed methods for gingko based on flavenoid analysis, and pomegranate based on elagic acid analysis. Other markers might be used, such as carotenoids, fatty acids, sterols and DNA, depending on the product and whether the test is needed, for example, to identify an ingredient or to show that its active chemical profile is maintained after processing.
This last point concerning stability is an interesting one. In Europe, dietary supplements are generally covered by food legislation and, as such, Article 3 of Directive 2000/13/EC require a "best before (end)" or "use by" statement on the label. By contrast, the FDA's Final Rule, does not appear to require an expiration date. It does however, refer back to the 2003 CGMP Proposal, which emphasised that, where an expiration date was used, it should be supported by appropriate data (68 FR 12157 at 12204). Here, it was recommended that manufacturers have a written testing program designed to assess the stability characteristics of the dietary supplement, and results of stability testing should be used to determine appropriate storage conditions and expiration dates.
As an aside, the Final Rule also notes that, "Crude botanical and other ingredients are inherently unstable and may lose their stability in even a short time unless costly temperature, humidity, and light controls are in place". This observation is made in a section dealing with shipments of ingredients. This raises the question of whether even an authentic ingredient necessarily maintains its activity prior to being incorporated into a product, never mind several months after the finished product has been distributed and a recommended use by date has passed.
This same observation can be made of a wide range of food ingredients, and pharmaceutical actives, and for this reason, stability studies are commonplace for both food and pharmaceutical products. Clearly, regardless of legislation and published best practice, any reputable company would want to conduct stability studies on its products, so as to be sure that the label accurately reflects the actual contents, both at the time of production and the likely time of consumption.
A stability study is actually something of a misnomer since its purpose is to detect signs of instability, and sometimes to create the conditions whereby any instability in the product or its packaging might be encouraged, accelerated and otherwise brought to light.
Within the pharmaceutical sector, stability studies are not only concerned with the shelf life of the end product but accompany and support all phases of drug development. This includes specific studies required to support progress through the various phases of clinical trials, though clearly, the clinical trials aspect does not apply to most nutraceuticals.
For nutraceuticals, the specific conditions chosen for storage will depend on the aspect of stability that is being assessed and the storage regime should, as far as possible, simulate the actual use of the product, and include testing at intermediate time points throughout the proposed shelf life period. Such tests might be physical (assessing changes to colour, clarity, particle size etc), chemical (assaying the active substance, degradation products, pH etc) and microbiological (total viable count, sterility, spoilage). The specifics of the testing regime are governed by a variety of factors. These include, but are not limited to, the particular characteristics of the product, and whether it is a new or existing product. In the latter case, the use of existing stability data may be permissible.
Needless to say, there is a vast range of chemical, microbiological, physical and microscopy tests that may need to be applied in order to assess the stability of a product and its packaging. For this reason, the relationship/partnership between the client and contract laboratory involves a high degree of trust and mutual support. The client must be willing to share potentially commercially sensitive information with the laboratory, possibly including the technical transfer of in-house analytical methods. The laboratory must be fully communicative throughout the course of the trial and particularly vigilant to identify and communicate any out of trend / out of specification (OOT / OOS) observations.
The complexity of the analytical challenges around ingredient identification, purity, authenticity and stability should not be taken as an excuse to ignore these issues. If the pet food scandal teaches us anything at all, it is that one rogue trader can damage the business of many well-intentioned manufacturers, and potentially, the health of thousands of unwitting consumers. Whilst some may think that the costs of testing are too high to bear, the costs of not testing could be very much higher, and ignoring the risks does not constitute any kind of safety policy.