FDA’s Requirement for NDI Notification Based on Products Instead of Ingredients

The Draft Guidance requires submission of an NDI notification by each and every manufacturer or distributor for each and every product that contains an NDI, rather than relying on general safety information and dosage parameters per ingredient for all products.

Theoretically, any variation whatsoever to the ingredients of a dietary supplement containing an NDI would require a new NDI notification. This approach is unwarranted.  FDA has historically permitted notifications based on ingredients, not finished products. For example, bulk ingredient notifications from suppliers provided recommended ranges for safe use of the NDI in finished products manufactured by their customers 

Companies that rightfully bypassed this step, relying on a previous FDA acknowledgement for an ingredient, should not now be required to come forward and submit a notification. Such a result would generate a regulatory logjam with no benefit to the consumer.

Treatment of “Chemically-Altered”

Processes that would not render an ingredient “chemically-altered” is unnecessarily limited. It appears to be generated using 1994 standards without accounting for any processes developed or improved since.

By requiring excess NDI notifications in this way, FDA would drive up production costs and stifle innovation as manufacturers would forego new technologies.

Treatment of Probiotics

Probiotics are a lawful and viable category of dietary ingredients. However, the Draft Guidance’s treatment of probiotics created using advancements in fermentation media causes concern of unnecessary exclusion of safe and effective species or strains.

Advancements in fermentation or production processes designed to improve culture yield and stability do not create an NDI.

Treatment of Synthetic Herbal and Botanical Ingredients

We disagree with FDA’s proposed treatment of synthetic herbal and botanical ingredients.  DSHEA’s definition of a dietary supplement outlines the ingredients a product can contain, including a vitamin, a mineral, an herb or other botanical, an amino acid.

Because synthetic versions of vitamins, minerals, and amino acids are already permitted, it is arbitrary and illogical to exclude synthetic versions of herbs and other botanicals in the Draft Guidance. As such, we hope FDA reconsiders this position.

The Draft Guidance Creates “Homogenized Products” and Discourages Innovation

We believe that if the Draft Guidance is adopted in its current form, the resources required to submit redundant, product-based NDI notifications will limit innovation by creating an environment where pre-approved, “canned” products will become the norm due to a less resistant path to market. While unfortunate, we believe this is a practical reality. This policy would encourage a marketplace lacking product differentiation where the consumer will have limited access to health-promoting supplements, contrary to Congress’s intent as conveyed in DSHEA.

As a supplement, it can often be found in products that support healthy mental function. Until recently, magnesium’s use in brain function was not fully elucidated.  However, with the recent discovery of Magtein®, research is now showing that brain magnesium levels are associated with optimal neurological support.  Magtein® has been compared to other sources of magnesium; most were unable to effectively raise brain magnesium levels.

The Science behind it…

In one preliminary study, Magtein® was shown to help support short term synaptic facilitation and long term potentiation, as well as supporting healthy memory and cognition function in both young and aged animals. A human double blind placebo controlled trial has recently been started at the University of Southern California, with preliminary results expected in 6-8 months.

Multivitamins

Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR. Dietary supplements and mortality rate in older women. Arch Intern Med. 2011;171(18):1625-33.

The first of the two articles was based on an analysis of data from the Iowa Women’s Health Study. This study, started in 1986, was designed to investigate associations between diet and lifestyle factors and the incidence of cancer in postmenopausal women. The current analysis examined the connection between supplement use and the risk of mortality in a cohort of over 38,000 women enrolled in the Iowa Women’s Health Study. The authors conclude that common vitamin and mineral supplementation by older women is of no benefit and is associated with an increased total mortality risk. The authors point out that the connection between supplementation and increased mortality risk was strongest for iron; however, they also found that supplemental multivitamins, folic acid, B6, magnesium, and zinc were associated with an increased risk of mortality. This has been portrayed by the media as new findings of the “deadly danger” of vitamins, and a further opportunity for those that believe the industry needs more regulation to advance their agenda. So, let’s put some things in context and better understand some key points about this study:

• This is an observational study spanning a 22 year time frame (1986-2008) and is not an intervention trial in which supplements were given. Observational studies are certainly not intended to determine cause and effect relationships.

• The use of supplements was obtained by subjects self-reporting their use at three times during the course of the study – 1986 (baseline), 1997, and 2004. In the authors’ analysis of mortality risk between the years of 1986 and 2004, if a subject reported supplement use during any of the 3 time points, they were considered to be a supplement user for the entire duration of the study. Certainly this methodology may not reflect long-term supplement use, as subjects could have discontinued or started supplementation that would not have been reflected in the analysis. Additionally, as the authors noted, supplement use changed dramatically during the course of the study. In 1986, self-reported supplement use was 62.7%, whereas in 2004 supplement use was 85.1%. Increased supplement use during the course of the study could have been the result of many factors, including self selection by subjects attempting to deal with failing health.

• The authors had to manipulate and adjust their analysis in order to find the negative associations that they reported. Supplement use at baseline was associated with a lower prevalence of diabetes, hypertension, and smoking as well as a lower BMI and hip:waist ratio. Supplement users were also more likely to have a lower intake of total calories, fat, and saturated fat and had a greater intake of grains, fruits and vegetable. When the data were analyzed and adjusted for age and energy intake, many of the supplements assessed were associated with a significantly decreased risk of mortality. It was not until the data were adjusted in an attempt to control for the variables associated with supplement use that the negative associations became statistically significant. However, in a statistical model it may be impossible to fully separate the healthful behaviors and characteristics that are associated with being a supplement user.

• The increased mortality risk from iron supplementation was mostly observed in subjects supplementing with greater than 200 mg/day. This level of supplementation is often associated with conditions such as anemia, for which there may already be an increased risk of mortality. This was not controlled for in the current study.

• The use of hormone replacement therapy was significantly greater in supplement users (13.5%) compared with nonusers (7.2%) during the duration of the study. While the authors attempted to adjust for this in their analyses, it certainly could have represented a confounding variable that could not have been sufficiently factored out of the analysis.

• Importantly, the manner in which the authors classified “nonusers” of supplements in their analyses is curious. They looked at 15 different supplement variables: multivitamins, vitamin A, beta-carotene, B6, folic acid, B complex, vitamin C, vitamin D, vitamin E, calcium, copper, iron, magnesium, selenium, and zinc. To assess the risk from a particular variable such as zinc, they compared the mortality in users of zinc supplements with the mortality in “nonusers” of zinc supplements. However, while the subjects in the “nonusers” of zinc category may not have been taking a standalone zinc product, many would have also been taking a multivitamin that contained zinc or supplements other than a standalone zinc product. As a result, in the analysis of risk for zinc users, the group against which they were being compared would have contained subjects who were consuming supplemental zinc. This point is not addressed in the study and could represent a serious limitation with respect to the interpretation of the data.

• It is interesting to note that very little attention is given to the fact that calcium supplementation was associated with a significant reduction in total mortality risk, cardiovascular mortality risk and cancer mortality risk.

These points highlight just a few of the questions and limitations that surround this study. The commentary accompanying the study is equally biased against supplementation and in general portrays supplementation in a negative light. We don’t believe that there is anything contained within this study that should cause one to stop taking their supplements, and in fact it raises more questions than it answers.

Vitamin E

The second recently published article was an analysis of data from the SELECT trial.

Klein EA, Thompson IM, Tangen CT, et al. Vitamin E and the risk of prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549-1556.

Similar to the multivitamin trial, the SELECT trial received significant negative media attention due to the reported finding of an increased risk of prostate cancer in those supplementing with vitamin E. The SELECT trial was a prospective randomized, placebo-controlled trial investigating if vitamin E, selenium, or the combination could reduce the risk of prostate cancer. Over 35,000 men at average risk for prostate cancer were randomized between 2001 and 2004 to participate in the study. Subjects were assigned to 400 IU/day dl-alpha-tocopherol (synthetic alpha-tocopherol), 200 μg selenium (from selenomethionine), the combination of the two, or placebo. A 2009 publication from the SELECT trial, with a median follow up of 5.5 years, revealed no statistically significant increase or decrease in prostate cancer risk among any of the groups. In 2008, the data and safety monitoring committee recommended that the study be discontinued because of “lack of efficacy for risk reduction…” The current publication is an analysis of the data taking in to account additional cases of prostate cancer in subjects through May, 2011. The authors reported a 17% increase in the risk of prostate cancer in the vitamin E group and did not find an increased risk in either the selenium or selenium plus vitamin E groups. A number of points should be understood in order to put these findings in context.

• The results of this study are in contrast to previously published randomized clinical trials including the Alpha-Tocopherol, Beta-Carotene trial (ATBC) and the Physicians Health Study II, which either found a reduced risk of prostate cancer or no change in risk.

• The results are also in contrast to previous trial including the CHAOS, HOPE, HOPE TOO and SPACE trials.

• It should be noted that the expert panel assembled by the American Institute for Cancer Research/World Cancer Research Fund (2007) examined a total of six cohort studies, 14 case-control studies, and one ecological study regarding the relationship between dietary and/or serum vitamin E and concluded that “there is limited evidence suggesting that foods containing vitamin E, and alpha-tocopherol supplements are protective” against the risk of prostate cancer. Importantly, none of these observational studies reported an increased risk of prostate cancer associated with vitamin E.

• A strange finding of the current study is that vitamin E was very specific for prostate cancer risk. No other increased risk of any other cancer, cardiovascular disease, diabetes or all-cause mortality was observed in the vitamin E group. The authors were not able to offer, nor does there appear to be any biological reasoning for the apparent specificity on prostate cancer risk. The authors also could not explain why there was no increased from the presence of selenium with vitamin E.

• No data on vitamin E levels were given so we don’t know the baseline vitamin E status of the subjects in any of the groups.

• Although the study was stopped in 2008, the current analysis includes cancers through 2011. We don’t know how many subjects continued taking supplements on their own and what impact the lack of supplementation over the past three years could have had on the outcome.

• Prostate cancer status was determined by self-reporting at 6-month intervals. The diagnosis was then centrally confirmed by the SELECT central pathology laboratory after obtaining the subject’s medical records. However, the authors state that 17% of the cancers were not centrally confirmed yet are still included in the analysis.

• The SELECT trial had an unusually small number of deaths from prostate cancer compared with what would be expected given the length of the study and number of participants.

• The form of vitamin E used was synthetic alpha-tocopherol and not natural-source alpha-tocopherol. We know that these forms of alpha-tocopherol are significantly different and are metabolized differently by the body.

As is the general rule, one should not rush to judgment based on the result of a single study, especially when it does not fit with the totality of the existing data. All of the evidence should be considered when making decisions about supplementation. Similar to the multivitamin study, many important questions remain unanswered in the most recent SELECT analysis.

You may already know…

Resveratrol is a naturally occurring plant polyphenol commonly found in grape vines and skins.  Highly regarded as a powerful antioxidant, it plays supporting roles in normal cardiovascular and mitochondrial function.  Studies also indicate resveratrol may be supportive in maintaining the normal aging process by helping to prevent free radical damage that can lead to premature aging of cells.

But are you aware…

Pterostibene is a methylated resveratrol that is naturally occurring in berries.  Some advantages over resveratrol include:

• Superior biological activity
• Better oral bioavailability
• Slower metabolism in the body

The enhanced activity of pterostilbene compared to resveratrol may be explained by structural differences.  Pterostilbene with two methoxy groups and one hydroxyl group has a greater ability to dissolve in fats, oils, lipids and non-polar solvents, and a higher potential for cellular uptake than resveratrol, which has three hydroxyl groups.

Pterostilbene also supports cardiovascular health.  In vivo studies demonstrate that pterostilbene possesses lipid and glucose lowering effects.

Two may be better than one!

Both pterostilbene and resveratrol support mitochondrial function and healthy aging by activating SIRT1, a key enzyme in a family of proteins that have been associated with influencing aging, energy efficiency, and alertness during low-calorie intake.

Researchers have suggested that these two compounds also work synergistically.  The combination of pterostilbene and resveratrol in a formulation may in fact be more effective than using these ingredients separately.

Better Health through Research

Our latest and largest research program to date, a $5 million multi-year commitment in collaboration with our strategic partner INAF (Institute for Nutraceuticals and Functional Foods), involves gaining a better understanding of Metabolic Syndrome and investigating the impact of nutrition on the prevention and treatment of the Silent Inflammation associated with this condition.

With our findings, we will be able to further develop and bring to market reliable, science-based products proven to help people in their fight against Metabolic Syndrome — and ultimately improve their quality of life.

This comprehensive Metabolic Syndrome research is just one of the many projects included in our corporate research program.

Learn more about Atrium Innovations’ commitment to better health through research: http://research.atrium-innovations.com

The manufacturing process itself is performed under tight controls by a team of highly skilled, dedicated staff, who strictly adhere to written Standard Operating Procedures (SOPs) prepared in accordance with Good Manufacturing Practices (GMPs), as listed under Nutritional Supplements in the USP32. All manufacturing takes place in temperature and humidity controlled conditions, and is under constant supervision. To further ensure precision and accountability, we electronically follow the entire manufacturing process, from the receipt of the raw material to the finished product. This allows us to track the progress of a product at all points through the production process and allows the various departments that work on the product to better interact, ensuring a quality supplement.

In addition to microbiology, our facilities have both physical properties and chemical analysis laboratories that ensure raw materials and finished products meet specific standards of quality, purity and safety. The physical analysis laboratory tests the weight, thickness, hardness, and disintegration of finished products, making certain that capsules and tablets disintegrate and release their nutrients in a timely manner. Using highly sophisticated analytical instruments, including HPLC (High Performance Liquid Chromatography), ICP (Inductively Coupled Plasma, used for mineral analysis), GFAA (graphite furnace atomic absorption spectrophotometry, used for heavy metals testing) and an FT-IR (Fourier Transform Infrared spectrophotometer), the chemical analysis laboratories test for the measurement of various vitamins, minerals and herbals to ensure that our products meet our meticulous standards of quality, many of which exceed the limits defined in the USP. Findings from our laboratories have been compared with independent lab reports on many occasions and have consistently been on target. In fact, many independent laboratories are often quite surprised and impressed when they learn the depth of our analysis capabilities and experience.

1. Does the CMO have a commitment to product quality and the expertise necessary to differentiate/innovate products?

When looking to partner with a CMO, the first thing that most people look at are the product capabilities. If you are a company who is looking to grow and diversify your product or brand, then you may want to look at the types of forms and delivery systems offered and find out what type of support your potential manufacturing partner can offer you. If they have a knowledgeable team that can help create science based supplements, you can be sure you are getting a quality product. Also, you may want a team that can make suggestions on new and revised formulations as they pertain to ingredients, product form and delivery, and packaging choices. No matter what your needs are, you want to choose a partner who will work with you to ensure that you are getting the best product to fit your brand’s identity.

Alcrea’s Solution: We manufacture traditional tablets, capsules and powders. More innovative product options are available in CapliquesTM (two-piece liquid capsules), liquid sprays, and other liquids. There are opportunities to further customize your supplement by using colors, banding, printed logos, flavors, and delivery systems for an end product that is unique to your brand. On-staff PhDs and scientific experts are available to assist you in formulating your product and overseeing the quality control during the manufacturing process. We strive to deliver supplements to fit our clients’ needs, as our product development and technical team weigh in with ingredient suggestions for higher efficacy, lower cost, or other suggestions in accordance with the parameters you define for your product.

2. Does the CMO offer a full range of services and how will that affect your cost?

The variety of services available can also be important when evaluating a potential manufacturing partner. Product variety will allow you to explore different supplement forms and delivery methods. In addition, it will benefit you in both time and cost savings if your CMO offers assistance in other areas. These may include scientific expertise for creating new applications or performing raw material/finished goods testing with on-site laboratories. Further offerings including marketing expertise and graphic design support can also be valuable as the manufacturer can fully integrate the processes necessary for delivering your product.

Alcrea’s Solution: We offer services and expertise from product development and manufacturing to quality control/testing and marketing. With our in-house laboratories, time and cost of testing your raw materials and finished products can be reduced. Also, we have the ability to custom design your label, custom package your nutritional supplements, and assist you in compliance review. Alcrea Health becomes a business partner, from product concept to ready-to-market product delivery, that enables a foundation for a mutually successful endeavor.

3. Is the CMO in compliance with FDA CFR III requirements for manufacturing?

It is not uncommon to see or hear about violations and warning letters being sent by the FDA to supplement manufacturers. While the process of mandating and enforcing this set of regulations is ongoing, it is important for both you and your consumers to have products manufactured in a facility that is audited for FDA compliance. Certifications/Accreditations and manufacturing procedures indicate a commitment to following regulations. Touring the facilities where your product will be manufactured, packaged, etc is also a good way to validate the company’s standards.

Alcrea’s Solution: Our manufacturing facilities are audited annually and hold many certifications including NSF GMP Registration, NSF GMP for Sport Registration, Danish Medicines Agency GMP Registration, Organic Certification, and Foreign Site Registration with Health Canada. Our on-site laboratories are ISO 9001 Certified and ISO 17025 Accredited. We also maintain Standard Operating Procedures (SOPs) that can be reviewed with clients during site audits and welcome potential and existing clients to tour our facilities at any time.

4. Does the CMO have a favorable reputation for credibility and consistency?

It is important to know how long your potential CMO has been in business and where your products will be manufactured. Some assume that contract manufacturers do not care about the ingredients that are put in a product and will not help when problems arise, which in some cases may be true. Not all manufacturers hold themselves to high standards of quality and integrity. You should expect consistency in the delivery and quality of your product and services that the manufacturer commits to. When you select a company to manufacture your product, you are becoming partners and it is important that you receive the level of service that you are paying for and can depend on them when issues accur.

Alcrea’s Solution: Alcrea Health has been in the business of custom manufacturing quality nutritional supplements for over 60 years. We are a publicly traded company (Toronto Stock Exchange) with sales of 425 million dollars forecasted for 2011. Our team understands what it takes to have a successful brand and goes to great lengths to be sure you receive the product that you agreed to.

5. Is personalized service and client confidentiality important to your CMO?

When working with a CMO, you want to be sure that you are treated as a valued partner in the development and manufacturing of your nutritional supplement. It is important that your contract manufacturer understands your goals and you understand their processes and how they will satisfy your needs. Also, it is important that you are aware of who you can reach out to. You do not want to be left with questions or concerns due to unreturned calls or conversations with someone who does not have knowledge of your project.

Alcrea’s Solution: We provide dedicated teams to each client so that they are always able to reach someone who is familiar with their account whenever needed. Also, we encourage face-to-face meetings so that all parties are on the same page and our team understands what is required of new products to coincide with your brand’s identity.

• Increased bioavailability of Vitamin D in liquid-filled Caplique^®
• Reduction of dosage size due to increased effectiveness
• Better results for the consumer
• Reduced costs as less raw materials needed

Why a Caplique^®?

Traditionally, Vitamin D has been manufactured in tablet form. By exploiting the technology behind our liquid-filled capsule, you are already on your way to providing a product with greater bioavailability in its delivery. Since Capliques^® are customizable, this dosage form also allows for many opportunities to fit your brand’s unique identity.

More about Vitamin D

Vitamin D is commonly known as the sunshine vitamin, the sun being the best natural source of the nutrient. However, most people do not get enough sunlight to produce optimal levels of this essential vitamin. You may be aware of the importance of Vitamin D for bone and skin care, but there are many other benefits.

There has been a lot of attention around Vitamin D recently, mostly due to studies focused on conditions such as cancer, heart disease and osteoporosis.

We are also seeing its importance in athletic performance and muscle function with studies done on professional teams and their players’ high levels of Vitamin D deficiencies.

Vitamin D enhances calcium absorption and has autoimmune benefits for rheumatoid arthritis and type 1 diabetes.

Ready to start creating your own branded VESIsorb^® Caplique^®?

Contact us to learn more

VESIsorb^® is a registered trademark of SourceOne Global Partners
Caplique^® is a registered trademark of Alcrea Health