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NDI, GRAS and Supplement Safety Assessment


The objective of NDI and GRAS  for supplements and foods is to provide a baseline evaluation of the safety aspects of an ingredient.

FDA issued draft guidance on the NDI and final guidance on the updated GRAS requirement in August 2016. The guidances are likely to require a significant amount of information related to safety and quality of dietary ingredients to be compiled and evaluated by scientific experts.

Four Steps to Compliance:

1. Determine the most likely regulatory status of your ingredient:  ODI, NDI, GRAS or other based on a preliminary review of regulatory status and toxicology data.
2. Compile a master file of all your safety and quality documents supporting the new CFR 117 and the new FDA guidances. Most master files are more than a hundred pages long, including references.
3. Have the master file reviewed for gaps according to the regulatory status. Perform a risk assessment to safety, quality or brand presented from the analysis.
4. Chart a plan of action to meet the requirements.
Toxicology and safety studies are expensive to conduct, so you need to know if your ingredients need to go through the new GRAS Notification process, require a NDI Notification, and also carry any specific risk for adulteration or contamination. Take care of these elements, and you can be fairly sure that you will not be blind sided by regulators, consumers, or class action attorneys.

A pre-assessment is typically conducted quickly to determine the appropriate strategy and level of risk.  Contact us to determine the best strategy for you.

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For more detail, here is a framework of basic requirements for a safety assessment

  1. Clinical, Medicinal and Food Use 
    1. In country to market
    2. Global
  2. Regulatory Status
    1. ODI or NDI (if ingredient used for supplement)
    2. GRAS
    3. Other
  3. Toxicity Summary
    1. History of human consumption in foods/supplements including dosage amount and composition
    2. LD50/acute toxicity/chronic/subchronic toxicity studies
    3. Bioavailability and ADME
    4. Clinical trials
    5. Other (genotoxicity, carcinogenicity, reproductive toxicity etc)
    6. Case reports, AER and Drug Interaction Review
  4. Dietary Supplement Manufacturing Risk Review (or CMC, Chemistry/Manufacturing/Control)

    1. Chemical and Nutritional Characterization
      1. Literature review
      2. Specification, Certificate of Analysis, ID and contaminants
    2. Manufacturing Facility GMP evaluation (self-assessment and audits)
    3. Potential adulterants and their controls

Contact us for more information.

Identity Testing for Dietary Supplements

by NaturPro in Quality Comments: 0

The mass confusion around identity testing has brought more awareness to the issue, but the industry is still lacking clear guidance on how to deal with some of the practical issues.

How to Properly Conduct Identity Testing for Dietary Supplements

Verifying identity is like a lot of sciences drawn from multiple disciplines: it’s not usually plug-n-chug, and it requires replication of results to achieve meaningful conclusions. Luckily for science, there are valid ways to determine ID. They just take some thought, and in many cases, more than one test.

The thought behind ID requires some understanding of the context of the material being identified. Species expected, plant part, physical form, likelihood and type of adulterants, degree of processing and concentration all dictate what type of method should be used.

Believe it or not, identity testing is easy for a lot of botanical raw materials. Whole or cut herbs, fruits and roots are often easily distinguished by their quality, and by physical features such as size, shape, color and odor. However, we lose this ability when we take a whole leaf, dry it and grind it into a powder whose parts cannot be identified by microscope. At this point, we have to switch to chemical testing to determine what ancient terminology should be used, using classifications created hundreds of years ago by people for plants.

Luckily, whatever form of ID methods we choose, we still need to compare to a ‘reference’ or a sample of the plant as it exists in nature. So it’s really important to be sure the reference material is authentic and representative of the target species in the population, because it forms the entire basis for the test. The method itself should be based on clear and objective pass-fail criteria that includes at least one positive match to the species expected, plus in many cases for higher risk materials, at least one negative match to rule out a possible adulterant.

The documentation is as important as the activity. If it’s not in writing then it didn’t happen, says the auditor. One shortcut often taken for verifying ID is to write ‘conforms’ on the COA. But what, exactly, does the sample conform with? A memory of what the sample looks and smells like? A powder that has been verified to contain some of the same chemical markers as the expected species, which you are ‘pretty sure’ is 100% of the expected species? Or to a specific authenticated reference material? Because shortcuts on the reference are so often taken, it is best to list the reference material number used in the Certificate of Analysis for the sample, under ID Method. Accompanying the COA and available on request should be a test report which lists all methods, reference materials and their validations and verifications.

How to know your reference material is authentic? The best is to acquire whole fertile plant parts from a source that has authenticated the identity of the sample using a trained botanist or herbalist. For chemical testing, a lower grade of botanical references (milled powder, extract or liquid forms) are often used, but their validity as reference material are considered inferior or secondary in the absence of authentication and chain of custody to the whole plant part.

The difference between trusting the source of reference materials versus verifying it can make all the difference. For example, a bottle of olive oil purchased from the grocery store may be used as a reference standard without verifying the identity with testing. However, olive oil is known to be adulterated with other oils, so our trust in the label should not be sufficient to verify its identity. We need more proof, in the form of independent test reports using valid methods, that the olive oil is 100% from olives and is not adulterated, before we can consider it a valid reference material.

Botanical references, even authentic ones, are not ‘ready-made’ to reference all types of samples from the same species and plant part. Again, this is an area that requires some thought by laboratory technicians. For example, when a botanical is extracted or heated, chemical changes occur. To prevent the processing method from falsely impacting the match, a reference must undergo the same process as the sample, or else the chemical differences from heating falsely appear as differences between the species. So, if your sample was extracted in hot 70% ethanol for five hours, then the lab should prepare the reference in the same way.

Now, for the top 5 ID testing lessons they don’t teach in school:

  1. Much of ID testing relies on a sufficient understanding of the material being tested. Communicate to the lab as much info as possible, such as specification and manufacturing process, so that they can make sure to prepare the reference standards correctly and select the correct method.
  2. No ID method covers all potential adulterations or mis-identifications. And ID covers contamination if it may be considered harmful. Make sure you know what the risks are for your materials. Risk assessment for adulteration is necessarily a team effort across the supply chain, not something that ‘someone else should be doing’.
  3. Authentic references and their preparation are as important (or more) than the method used. Always check the sources and make sure they are authenticated and representative of the species and identity.
  4. Testing the same sample with different methods substantially improves the meaningfulness of any one test. High risk materials with known adulterants often need a test for a positive match to the species and a separate test for a negative match to the adulterant.
  5. Many adulterants, especially newly developed ones, are not caught with typical ID methods, which is why strong specifications, and supplier verification is so important.

The issue of ID is not going away, and it’s a big issue in food now too (see sawdust in cheese, sushi that’s not sushi, etc). The wave of attention on food and supplement ID issues has not yet begun to crest, but now at least we know how to swim.

This article was originally published by Natural Products Insider in August 2016.

Dose Delivery: Oil Into Water


The gut is by nature one of the best machines imaginable for chemical conversion of food into energy. As a result, the majority of what we consume is changed into something different with incredible efficiency. The stomach begins this process with the pH of battery acid, plus enzymes. Then, the intestines—25 feet long and filled with hungry bacteria and more enzymes— do the rest. Considering the environment, it is surprising that anything we consume actually absorbs into our bloodstream intact.

Bioavailability, often defined as the amount of a compound put into the body compared to the amount reaching blood circulation, is an unexpectedly complex subject. Luckily, the pharmaceutical scientific literature has given us some good tools to understand it adequately.

In order to be bioavailable, a compound must first remain stable and retain its identity in the gut, which is no small order. Assuming it stays intact, its bioavailability can be divided into four main classes, categorized by the Biopharmaceutics Classification System (BCS). According to the BCS system, there are only two chemical factors driving bioavailability: its solubility and its permeability. Water-soluble compounds like ascorbic acid are considered class I (high solubility and permeability), the ideal scenario for bioavailability. However, many fat-soluble compounds such as curcumin are considered BCS Class IV, possessing low solubility and permeability. With the potential of curcumin and its more than 6,700 published studies, this means a lot of opportunity in the face of a lot of challenge.

For Class I to III compounds, dose delivery is often fairly easy to solve. Optimizing these based on pH, particle size, solid dispersions, crystallization or salt forms can be enough to ensure adequate absorption. But what to do about the difficult Class IV compounds?

The water solubility of a compound is based on its chemical polarity, which depends on the electric charge of a compound (given by the presence of charged atoms like oxygen) and its asymmetry. Water (H2O) is polar, because it’s an asymmetric molecule containing mostly oxygen by weight. On the other hand, fats and oils, generally symmetric compounds with a lot of uncharged carbons, are nonpolar and not very water soluble.

The spectrum of polarity includes some compounds called amphiphilic (meaning both-loving) which are able to interact with both polar and nonpolar compounds. As a result, they are ideal to include in many dose-delivery systems. Because ‘like dissolves like’, amphiphiles can dissolve both fat- and water-soluble compounds; detergents like soap, which dissolves grease into water, are one everyday example of this type of compound.

The use of amphiphiles to improve bioavailability has already been perfected in our gut. High-purity phospholipids are the key components used by the small intestine to absorb dietary fat. Phospholipids are also a main part of cell membranes, whose critical function is to separate the cell from its environment while at the same time allowing both polar and nonpolar nutrients to pass through. In the past few years, science has harnessed these unique and interesting properties of phospholipids to better deliver active compounds to target tissues.

To date, thousands of studies have been published on improved bioavailability technologies such as solid-lipid particles, nanoparticles, micelles, liposomes, emulsions, microparticles and others. Phospholipids are one common factor among these technologies, which ultimately stabilize and solubilize compounds of a class IV nature. Curcumin, resveratrol and other fat-soluble compounds all clearly benefit from some of these advanced dose delivery systems.

Yet challenges remain. In the view of the literature and medical use, reliable human efficacy is achieved infrequently; the number of successful human studies using these advanced technologies pales in comparison to the number of successful test tube or animal studies. Why? From a dose delivery view, it is also well understood that there is an ideal concentration of active in the body: too little is ineffective, while too much may be counterproductive. Striking that balance is a difficult task.

The human body and how exactly it works remains much of a mystery, still with vast areas of uncharted territory. And some big differences exist in how we absorb, metabolize and excrete what we consume, due to genetics, diet, what we consume it with and other variables. Plus, each active compound is an individual chemical entity with unique physicochemical characteristics and bioavailability. Hence, the need for good and rigorous science.

Also, our current capabilities and standards for measuring bioavailability are sometimes not relevant to efficacy. For example, bioavailability of fat-soluble compounds is generally measured in blood plasma, because plasma is mostly water-based and the best medium to measure water-soluble compounds. However, plasma data often does not reflect actual bioavailability of fat-soluble compounds, because plasma does not generally attract these compounds like blood cell membranes and organ tissues do. Many dose-delivery technologies work magnificently in the test tube, but may not survive stomach acid or the small intestine intact. And some delivery systems may appear to improve bioavailability but only for an inactive metabolite like a glucuronide.

In these cases, the chemical identity of what we measure in the blood, in addition to what part of the blood we are measuring, proves to be more important than the amount we are measuring. When the science of a bioavailability study is off-kilter, it can ultimately lead to the selection of poor clinical study material and a failure to show efficacy. Good science in the early stages of development is critical, and while oil and water can mix, dose delivery is ultimately just a means to promoting health.

By: Blake Ebersole

This article was originally published in Natural Products Insider in August 2014

 

Supplier Verification Key to New FDA Rules

by NaturPro in Quality Comments: 0

Long before the New York Attorney General made a move to DNA test mainstream supplement products (and well before the Dietary Supplement Health and Education Act of 1994 [DSHEA], 21 CFR 111 and now CFR 117), foods and supplements were prone to adulteration—both deliberate and unintentional.

In today’s modern supply chain, ingredients generally come in powder or liquid form, masking their true identity to the naked eye. They are shipped from afar—and grown and processed from even farther. Their travel across dusty roads and through busy ports is accompanied in many cases simply by a piece of paper that “certifies” their analyses.


Contact us about independent supplier auditing and verification with Supplier Verified


The adulterants of today are similar to those of yesterday, but more advanced. Undeclared fillers and analysis-interfering ingredients are today’s sawdust and snake oil. And even raw materials innocently misidentified or mistested can ruin all the good intention in the world.

“Caveat emptor,” say some suppliers, “I don’t confirm my supplier’s certificate of analysis (CoA) because that’s my supplier’s job.” Passing the buck doesn’t—or shouldn’t—work in today’s regulated industry. A money-back guarantee cannot erase the taint of inferior ingredients consumed by people daily, and in relatively large amounts for their health.

When the analysis certified by that piece of paper is a third- or fourth-hand document whose validity has not been independently verified or tested, a shred of trust quickly turns into a shroud of mystery: Who tested the material? How did they test it? Can we trust the results?

On another part of the supply-chain spectrum exists a lot of upstanding, quality-invested companies, which simply come from the old days and have not accumulated sufficient expertise or information about how their ingredients are made or tested. Now we are made to actually test against the spec instead of trusting it—isn’t that enough?

Not anymore. Many are damning the attorneys general for their lack of expertise about the uses and limitations of DNA testing of botanicals. But others believe that their actions, and the new FSMA (Food Safety Modernization Act)/CFR 117 rules serve not as a red herring, but a beneficial spotlight on some real issues: What tests are suitable for identity? How do we ensure identity and ingredient integrity is maintained?

Many of those who are committed to quality see the rainbow in the storm, and want to invest in doing the right thing as part of continuous improvement. They know transparency and traceability are not just buzzwords: the concepts actually mean something to CPG (consumer packaged good) marketers—and not just because they are starting to mean something to the end consumer.

The new requirements have a catch: maintaining and improving on the principles of transparency and traceability requires more than just creating product specifications and testing against them. Adopting these values to meet the new requirements will require investment in strong relationships and control of supply chains, and proper audits and qualification of suppliers. Trust but verify.


More about verification of specifications using Spec Verified


Now that many U.S. manufacturers are getting up to par on GMPs (good manufacturing practices), FDA appears to be (rightfully) focusing on suppliers of ingredients imported from foreign countries such as China and India. So, under the new CFR 117, supplier verification programs are required. Some say the new requirements, which also require verification of food safety principles like HACCP, are the missing link between the requirements of DSHEA and how to responsibly ensure food and supplement product safety and integrity.

Here’s one example to illustrate: many factories overseas performing extractions also process pharmaceutical actives, including cytotoxic drugs and other materials that can possess bioactivity at low concentrations. These materials, which could cross-contaminate a natural product brand’s material, are rarely listed on the specification. The reason stated for the absence of cross-contaminants on the spec is that they are unnecessary—because cleaning is performed between manufacturing runs. But how is the validation of the cleaning performed? Are all nooks and crannies of the production line cleaned? A weak cleaning validation or pre-production line clearance, lacking any actual limits or in-process testing for contaminants, serves as a key difference between a safe, legal product and an adulterated, potentially unsafe one.

Ingredient manufacturing facilities should perform cleaning validation, and should let their customers know of potentially toxic products that are made on the same production lines. This information isn’t found on the ingredient specification, but is part of a good supplier qualification program. If a brand doesn’t ask about cleaning validation or audit the facility’s production records, it would never know whether the cleaning was effective to prevent adulteration or a potential product liability issue.

“Trust but verify” is the central mantra of GMP and of good quality practices. For these reasons, and many others, many experts believe the new CFR 117 is a critical and important move toward improving product quality and integrity in dietary supplements. So, if the industry in 2015 is remembered by the word “identity,” 2016 may be known for the words “supplier qualification.”


Contact us about supplier verification with Supplier Verified


If a brand isn’t well-versed in these areas, help is available. New compliance programs offered by groups such as NSF International, IDDI and others work to close gaps by offering independent review and verification of supplier GMPs. Others focus on verifying ID and product specifications, based on oft-cited FDA inspection violations. New independent supplier verification services are available to assist clients with meeting the new rules.

Once, during a foreign-supplier qualification audit, I politely noted a potential risk to product safety that was due to the absence of a critical control point. After the facility supervisor’s response along the lines of “it’s not a big deal—we have never had a problem noted,” I acknowledged that may be the case. But now knowing the potential risk, would he let his children consume the product without fixing the issue? There was a pause in his response.

Likewise, we should all be willing to swallow the product whose safety and quality we are responsible for. But before taking the plunge, we should get to know our suppliers, and verify their quality practices.

By: Blake Ebersole

This article was first published by Natural Products Insider, December 2015.

Traceability: What’s the Point?

by NaturPro in Quality Comments: 0

Traceability is an industry buzzword, quality issue and regulatory requirement for products intended for human consumption, with the latest focus fueled by adulteration of baby formula with melamine in 2008 and the subsequent signing of the Food Safety Modernization Act (FSMA). Quality issues that can be solved by traceability systems date back at least 2,000 years ago, when Dioscorides developed methods to differentiate Balsamodendron (balsam), Commiphora (myrrh) and Boswellia (frankincense) gum resins. Likely due to early traceability and quality systems, the Magi were able to differentiate among these valuable materials with similar visual and sensory attributes:

Balthazar: Melchior, you say this material is frankincense, but how do you know for sure?

Melchior: This material has met the basic quality requirements of our time: it is easily flammable, with clear smoke and pleasant, characteristic fragrance. Also, my supplier harvested it from his Boswellia tree just this morning. This information is written on parchment with his signature.

Balthazar: Your argument is convincing, and you have established adequate traceability. Let us approve this material fit for its intended purpose.

Today, there is no definition or standard for traceability. Traceability systems are intended to track the flow of materials through the supply chain, and are mainly made of documentation and the supporting legwork done to create and verify the documents. The ISO 9000:2000 guidelines define traceability as the “ability to trace the history, application or location of that which is under consideration.” For some food systems, traceability is maintained back to the farm or even the seed, while in others it is maintained back to a point in a manufacturing process intended to control a key quality attribute—microbial load, for example.

Traceability requirements depend on the type of product and the regulations of various countries. In Europe, documentation is required to identify suppliers of ingredients of foods. In the United States, FSMA requires the country of origin to be labeled. However, for the U.S. dietary supplement industry, ingredient traceability systems at reputable firms go beyond country of origin, requiring the name and address of ingredient manufacturing facilities, and product quality and traceability information that in many cases requires a chain of custody back to the farm.

In general, the requirements for traceability in the industry differ widely, depending on the type of product and market demands. For example, a small volume of conventional chamomile tea made only from dried chamomile flowers sourced from a single farm and sold at a single local market can have a very simple (yet effective) traceability system: “I know the farmer who grew and dried these flowers.”

On the other hand, coffee that is mass-marketed in high volumes for attributes like shade-grown and fair-trade will require a relatively complex and resource-intensive system, particularly as higher volumes are demanded. This is because of the multiple steps in the supply chain and the fact that many coffee farms are small—so a large number of farmers need to be supervised and documented, which can be a costly endeavor. However, coffee that is labeled simply as Arabica need not have any traceability other than that required to maintain product quality and safety.

Even within a traceability system, there are different strengths of the supporting documentation. Statements from the raw material buyer that a fair price was paid to the harvesters serves as one layer of support, but solid verification of this claim may require an in-person audit of the system and periodic visits with the individual farmers and harvesters. How far does a brand want to go?

Ultimately, “full traceability” is difficult to achieve for agricultural products (until we can figure out a way to bar code each individual plant). So, the objectives and costs of an adequate traceability system depends on the nature of the product and market demands. Three main objectives for traceability systems include:

1. To effectively manage the supply chain: Supply chain management aims to determine the most efficient way to produce and procure products. Documentation of the products throughout the cycle from start to finish is key to understanding how they are made and how much they should cost.

2. To support marketing claims: Today’s discerning consumer demands many attributes from their products, which they are not able to taste or otherwise perceive in the product. For example, dolphin-safe tuna can only be verified through the supporting documentation; no analytical test is available to test that the tuna is dolphin safe.

3. To provide information for quality assurance systems or food safety investigations: When product quality issues occur, traceability documents are integral to track back to the root cause of the issue and correct it.

In the world of botanical ingredients, traceability may extend all the way to the farm, while for agro- or petrochemicals, it may extend back to the manufacturing level. Regardless of the level to which a material is traced, one of the key requirements for any system is based on the concept of segregation, which for the purpose of determining GMO (genetically modified organism) status is known as identity preservation. In proper systems, materials have discrete lot number and sizes, and are kept physically separate from other materials or inputs.

In determining lot size, there is a balance that takes into account the level of “precision” required for a product. Too few lots for a given amount of material, and the amount of material may be too large to control and keep consistent; too many lots require legwork and testing that may be too costly. Ultimately, the customer sets the expectation for traceability and will value (and pay for) the benefits and peace of mind that it can offer.

By: Blake Ebersole

This article was originally published in Natural Products Insider in November 2014