Upcoming Issue Highlights

Without a Trace?

Compliance & Quality Compliance & Quality
AIDP

Not if the natural products industry has anything to say. Manufacturers and experts silence the critics by taking ownership of all facets of compliance and traceability.

The Participants Are:

• Tony Blanch, Director of Quality and Corporate Services, Nutraceutix, Redmond, WA

• John B. Atwater, PhD, RAC, CQA, Senior Director USP Verification Programs, United States Pharmacopia (USP), Rockville, MD

• Christen Davis, Senior Quality Assurance Manager, Capsugel, Greenwood, SC

• George Pontiakos, President and CEO, BI Nutraceuticals, Rancho Dominguez, CA

Compliance and quality are essential to maintaining consumer trust in the natural products arena. NIE discusses with industry experts the current status and where improvements can be made. NIE: What are the biggest challenges to compliance and transparency for finished product manufacturers and suppliers: claims, GMP (good manufacturing practice) standards, sourcing, or something else and why?

Pontiakos: Compliance and transparency start at the source and continue throughout the whole supply chain. Since adulteration and contamination can occur at any point in the supply chain, every point is linked and presents a challenge.

Sourcing is the most complex function of our industry; not only because the raw materials and ingredients are geographically dispersed, but because of differing currency, language, local regulations, quality, seasonality, weather and much more. Once sourced, manufacturing processes can influence compliance and transparency.

Cross contamination with other products, environmental contamination, mix-ups, and mislabeling could lead to poor quality material. These can be avoided by implementing good manufacturing practices.

Blanch: Evolving customer perceptions of quality and compliance are a significant challenge.

Vocal consumer groups can drive product managers to ask for layers of raw material and product compliance that may be poorly defined, may compromise supply chains or product stability, or legal liability.

Recent examples include GMOs (genetically modified organism), gluten-free claims, total and added sugars, ‘free of’ or ‘Made in USA’ claims.

The GMPs have been in place for several years and dietary supplement contract manufacturers should be fully compliant.

Dietary ingredient suppliers should be well along the path to FSMA (Food Safety Modernization Act) compliance with some tweaks to their current traceability and security programs. Davis: Based on individual customer feedback as well as a recent Capsugel survey of 90 manufacturers and developers, the top concern among product manufacturers and suppliers is understanding the regulations for claims.

An example is ‘clean label’ claims, a sensitive subject for many consumers. Despite the wide recognition of the term ‘clean label,’ there’s no clear definition. Clean-label consumers, however, expect these ingredients to be limited, more natural, less processed, made with familiar ingredients and clearly labeled. But without specific guidelines, product manufactures and developers resort to ‘free from’ proxy wording—‘free from’ preservatives, allergens, gluten, additives, pesticides, artificial sweeteners, artificial colors, artificial flavors and genetic modification, to name a few. They also look to certifications to communicate quality to this consumer segment, particularly vegetarian, vegan, non-GMO, kosher, halal and organic.”

Atwater: One of the biggest challenges to compliance and transparency involves GMP standards and sourcing as it relates to the quality of dietary ingredients and dietary supplements. The current GMP requirements provide limited assurance that the dietary ingredients and dietary supplements are of adequate and consistent quality across different manufacturers who establish their own private quality standards. Stronger adoption of USP’s science-based public quality standards by the industry or in the regulations would provide a solution to this issue.

Public health is best served when public standards for quality are required as a minimum, as is the case with drugs in the USA. Universal adoption of the USP-NF science-based public standards would serve regulators (e.g., FDA), manufacturers and consumers by improving the consistency and quality of dietary ingredients and dietary supplements marketed in the USA.

NIE: Concerns are sometimes raised about vendors and raw materials from the Asia Pacific region. What efforts and initiatives do you feel will improve the confidence of manufacturers, retailers and consumers in the quality and purity of these ingredients and suppliers?

Pontiakos: BI’s concerns are never geographic focused; they are supplier/grower focused. There are professionally managed quality suppliers in every region worldwide. BI’s Identilok Program ensures suppliers are compliant irrespective of location.

To improve the confidence of manufacturers, retailers, and consumers in raw materials sourced globally, suppliers need to have a stringent vendor qualification program.

Quality and purity should start before the raw materials even enter a supplier’s facility. A good vendor qualification program provides clear guidelines on specifications, test methods, and product quality to vendors; regular audits of the manufacturing and lab facilities to assure compliance with GMP and GLP (good laboratory practices); random audits of traceability to assure usage of correct raw materials; random sampling and testing to ensure compliance with specifications; and oversight of the vendor’s entire QA/QC (quality assurance/quality control) program.

Once raw materials enter the supplier’s facility, the product should be tested before, during and after production.

At the same time, manufacturers also need to make efforts and initiatives to improve the confidence of retailers and consumers by choosing the quality supplier. If a supplier does not allow you to audit their facility, a manufacturer should question that. If a supplier has a price point well below the market price, a manufacturer should question that. Quality requires capital investment.

Atwater: The Food Safety Modernization Act (FSMA)—which was signed into law in 2011 and the corresponding regulations that the FDA (U.S. Food and Drug Administration) will begin implementing in September 2016—are expected to have a major impact in helping ensure the quality and purity of ingredients in the supply chain, both in the Asian-Pacific region and elsewhere in the world.

The intent of FSMA is to proactively prevent contamination and adulteration rather than reacting to it.

Two major changes that FSMA is implementing are the new food GMPs in 21 CFR Part 117 and the foreign supplier verification program for importers of foods. These two activities will be centered on hazard analysis and critical control point (HACCP) risk assessments rather than end-product testing, which for some manufacturers will represent a paradigm shift. Blanch: Contract manufacturers that are GMP compliant should already have raw material qualification programs in place that evaluate and approve vendors and manufacturing sources of ingredients and should be monitoring those ingredients through testing for identity, purity, strength, and known possible economic adulterations.

Advertising copy that educates about these programs would go a long way to inform the consumer that we are doing everything possible to protect them in the sourcing of materials. A campaign like this should include language that there are economic trade-offs driving the sourcing of materials from other regions of the world and these costs would naturally be passed on to the consumer.

Davis: Capsugel has a supplier certification program that includes several key steps in the verification of a supplier from any region of the globe to assure it meets our stringent cGMP screening that the material supplied is safe, pure and effective. It includes:

• Creating a purchasing specification based on a validated method and assuring the supplier can meet it.
• Thorough review of all documentation and descriptions of manufacturing processes.
• Obtaining certifications from third parties like NSF cGMP, ISO 9001-2008, etc.
• Obtaining three consecutive lots of materials to test against the purchasing specification.
• Performing onsite audits.

All our vendors must go through the same level of scrutiny and meet the same standards as part of the FDA guidelines.

NIE: Analytical labs play an important role in testing for heavy metals, toxins and other contaminants. Discuss why this is so important.

Davis: Analytical laboratories are important because they secure the safety and security of the global supply chain. They ensure that regulatory specifics are met, regardless of where raw materials and ingredients are sourced. By verifying results, analytical laboratories provide confidence to manufacturers, the overall market, and ultimately, the end-user consumer.

Capsugel considers such analysis so critical that we have conducted our own testing of our capsules, both ingredients and final product, for our customers. As an industry leader, we have deployed state-of-the-art technologies to monitor elemental impurities, technologies that are now showing up in regulatory and compendia guidelines around the world.

Atwater: Analytical labs perform testing for chemical and microbiological contaminants that help manufacturers determine whether or not they have the appropriate in-process manufacturing controls to reduce or eliminate known, or suspected, contaminants to acceptable levels.

In order to obtain accurate and reproducible test results, the lab should use validated test methods that have been shown to be suitable for use for the product being tested. USP General Chapter <1225> Validation of Compendial Procedures and <1226> Verification of Compendial Procedures provides guidance to help laboratories ensure that their test procedures can produce accurate and reproducible test results.

USP also provides test procedures and acceptance limits for several types of contaminants in dietary supplements, including the following for heavy metals and microbiological contaminants: USP General Chapter <233> Elemental Impurities—Procedures; <2232> Elemental Contaminants in Dietary Supplements; <2021> Microbial Enumeration Tests—Nutritional and Dietary Supplements; <2022> Microbiological Procedures for Absence of Specified Microorganisms; <2023> Microbiological Attributes of Nonsterile Nutritional and Dietary Supplements.

Blanch: Many times the contract manufacturer does not want to make the large investment in resources to perform these tests themselves, or their clients prefer to receive reporting from an independent source. Also having an approved backup lab can help when the company lab is over capacity or with new or novel testing method development.

Pontiakos: It is far more important to have a supplier that has the analytics in-house, relying on outside lab services is a poor path to ensuring a quality product. Defending your marquee is a function of the professionalism of your supplier, not on an outside lab result.

NIE: What are clean-label supplements and what are some of the best examples of this trend today?

Atwater: Clean-label supplements can have a different meaning for each of us, but generally, a clean-label supplement means a product that has undergone minimal processing and does not contain artificial ingredients, genetically engineered ingredients, and synthetic ingredients with chemical sounding names. The best examples of clean-label supplements are supplements made in large part with nutrients derived from whole foods.”

Davis: In order for a supplement to be considered clean label, the entire dosage form needs to meet their claim requirements, including the capsule when the product is encapsulated. Global consumers look for this, too, preferring vegetarian capsules, now desired by 38 percent of supplement users, according to SORD studies.

But not all vegetarian capsules are alike. Capsugel’s portfolio of vegetarian capsules meets the clean-label expectations. Encapsulated products can be free of binders, fillers, and undesirable excipients. Our capsules are free of gluten, allergens, artificial colorants, starch, and preservatives, as well as vegan-approved, non-GMO, and certified by the Vegetarian Society. The selections include the low-moisture Vcaps and Vcaps Plus (HPMC) capsules, for moisture-sensitive fills and dry herbal products; the acid-resistant DRcaps capsules that are an ideal solution for probiotics and enzymes; and the pullulan Plantcaps capsules that provide a more natural way to mask pungent odors like garlic and protect oxygen-sensitive ingredients.”

Pontiakos: Clean label is an ambiguous term; there is no formal definition. However, most consider clean label as few, free-from, and minimally processed ingredients as well as natural alternatives to artificial colors, flavors, and preservatives. In the dietary supplement market, clean label is usually associated with whole food powders that inherently contain the desired functionality and/or nutrient like acerola powder with naturally occurring vitamin C instead of straight ascorbic acid.

NIE: What about ready-to-use premixes and semi-finished product for custom manufacturing? Are there special quality or transparency challenges inherent in product formulations such as these?

Pontiakos: There are definitely special quality and transparency challenges when it comes to ready-to-use premixes and semi-finished products. The closer a product is to a single-component whole form, the easier it is to identify it and detect adulteration and contamination.

Natural ingredients are already complex products to begin with, and multi-component blends make it more complicated. To address these challenges, manufacturers should partner with a supplier who is well-versed in ready-to-use premixes and semi-finished products and provide them with as much detail as possible from the very beginning like the botanical species of each ingredient, proportions, and allowable excipients.

Blanch: In premixes and blends of multi component dietary ingredients (think enzymes or herbal/botanicals, probiotic blends, etc.), assaying for strength can be challenging, but we find assay for identity is most vexing. Under GMP rules, identity must be confirmed on each receipt of a dietary ingredient.

Complex multi-component blends may interfere with identity testing, or small percentage components may simply be impossible to retrieve from the blend matrix. This can be especially difficult when the blend is ‘proprietary’ in nature and the manufacturer is resistant to disclose formulation.

In some cases, it is possible to work with the supplier to provide acceptable traceability reporting for identity testing of premixes and then confirm identity based on the reporting from the manufacturer and testing against a custom standard for the blend. In many cases it is easier to buy the individual components, test them, and build the blend yourself.

Atwater: In general, ready-to-use premixes and semi-finished products for custom manufacturing have the same quality and transparency issues that concern ingredient suppliers and finished product manufacturers.

Ready-to-use premixes and semi-finished products are just in-process manufacturing materials. However, there are only a few public quality standards for such materials (e.g., Lutein Preparation USP). One should ensure that the ingredients used in the preparation of premixes and semi-finished products comply with appropriate quality standards, e.g., USP-NF and FCC standards.

NIE: What are the steps that raw material suppliers and manufacturers should follow from soil to shelf to ensure quality and traceability?

Davis: Capsugel insists on security of capsule raw materials. Our Supplier Selection and Qualification Program guarantees that our hard capsules meet the highest standards for quality, traceability, and integrity. This core five-phase program requires critical key raw materials suppliers to undergo an intensive, yearlong selection and qualification process to make sure they meet the most stringent regulatory and industry standards that exist anywhere in the world.

Here are the five components:

1. Preliminary Investigation: Reviews the supplier’s quality system, state of manufacturing technology and scope of products and services offered and determines the supplier’s performance metrics in details.

2. Manufacturing Suitability Evaluation: Assess the crucial issue of whether the supplier’s raw materials is compatible with Capsugel’s manufacturing processes and protocols

3. Production Trial: Use of supplier’s raw material in large-scale, high-volume production trials at various Capsugel sites to confirm both finished capsule quality and manufacturing efficiency performance levels.

4. Onsite Audit: Full traceability exercise and quality system check to ensure compliance with applicable and Capsugel standards

5. Acceptance Contract: Formalizes the technical and commercial requirements and expectations, including both initial scale-up support and ongoing quality

Once suppliers are selected and qualified, we consistently monitor them to ensure ongoing quality. The evaluation process assures supply chain traceability and finished capsules that comply with the highest standards. The management involves constant testing and regular in-depth onsite audits.

Blanch: Know your suppliers—where are they getting materials from, are the supplies stable or are they sourcing from whoever is providing this month’s low bid? Educate your suppliers about the changes coming under FSMA and help them to understand that compliance is not optional, and in fact will eventually be demanded by more than their dietary supplement manufacturing clients, it will come from their food clients as well.

NIE: Discuss food and ingredient authenticity. What needs to be done to make sure that economic adulteration and other issues are addressed and overcome as an industry? Pontiakos: First, we not only need to acknowledge economic adulteration and other issues exist but also their prevalence. An issue that is not acknowledged to its full extent is an issue that will not be addressed and overcome.

Ever since the actions of the New York attorney general last February, lively discussions regarding economic adulteration and how to improve our industry have been more commonplace in client meetings, industry conferences, and the media. Second, we need to improve our standards as a whole, from the vendor who provides the ingredient to the manufacturer who chooses which ingredient to purchase to the industry association who provides training to the FDA who upholds the standards.

We, as an industry, understand that providing safe product is both an individual and team effort—each organization must do its own part to build a quality supply chain. One bad link disrupts the whole chain.

Atwater: The presence of products spiked with synthetic drugs marketed as dietary supplements demands the use of innovative tools to protect public health.

USP has responded to the challenge by developing General Chapter <2251> Adulteration of Dietary Supplements with Drugs and Drug Analogs.

Also, the USP food ingredients intentional adulterants expert panel recently created the Food Fraud Mitigation Guidance (FFMG) that provides manufacturers and retailers with a comprehensive, practical four-step approach to help perform a vulnerability assessment and develop a customized food fraud mitigation plan. FFMG can help suppliers address some of the requirements of FSMA.

Blanch: Where there are test procedures available, raw material testing as part of new qualification and periodic monitoring should help root out the bad players. Specialized contract labs almost always have a better understanding of current issues in adulteration and how to overcome it through testing. The industry needs to implement a zero-tolerance stance to economically adulterated materials, even when the manufacturer doesn’t know where it entered their supply chain.

Davis: Part of Capsugel’s Supplier Selection and Certification Program is to make sure we are receiving what we ordered as it should be with any supplement manufacturer. One way to ensure this is to outline contractually enforceable purchase specification standards based on worldwide regulations and guidelines.

Some of the key standards are:

• Strict purity criteria
• Impurity limits to include contaminants, elements, and solvents
• Viral safety guarantees for animal-derived ingredients (in our case, bovine for capsules)
• Biological safeguards as it relates to GMO
• Controlled use or absence of allergens

NIE: Auditing, testing of food ingredients/supplements and training of production/QA/QC personnel. What do we need to focus on in these areas, big picture, and some best-case examples?

Blanch: Choosing a supplier or manufacturer with audited certification or registration of GMP processing is a good first step, especially if you understand the certifying body’s requirements for compliance. Do they follow up on corrective actions, what is the frequency of audits? Is it a dietary supplement or food sanitation assessment? Is the program rigorous enough to allow you to forgo auditing yourself? Adequate training is always a challenge for production facilities and should be part of their GMP program. There should be basic sanitation, PPE, and safety training before starting work, followed by intensified or specialized training on the job. A high employee turnover rate may be an indicator of dissatisfaction, or may be related to growth and transfer opportunities; in either case retraining new staff members can put a burden on managers and potentially compromise product quality.

Davis: Following a Quality by Design model, Capsugel partners with its manufacturing customers to establish processes that will help them to become more self-sufficient and successful. As part of this model, our Quality Engineering Services (QES) can collaborate with them through the entire manufacturing process—from receiving raw materials to supplement applications and production to improving capsule filling productivity for improved profits.

For example, we can conduct an audit of a manufacturer to assist them in setting up a regulatory foundation for their operation.

Another example is assistance in capsule-filling operations, either at original setup or to troubleshoot a problem. Matching a capsule-filling machine and capsule for the specific formula has proved to increase filling speed and yield while reducing downtime.

In 2014, a survey of 41 Capsugel customers showed a combined aggregate savings of $10 million through improvements in productivity through this model—or $251,000 average per company. With an average capsule spend of $162,000, this represents a 155 percent recovery of the cost of the capsules simply by implementing improvements based on the model.”

Pontiakos: For auditing, the focus should be on GMP standards. Vendor’s SOP (standard operating procedure) programs, testing capabilities, laboratory equipment, sanitation program, process control, pest control program are some of the areas that should be evaluated. It is necessary to assess whether or not the vendor follows some form of GMP and GLP in terms of product and document traceability.

For testing, the focus should be on test method. It is very important for manufacturers to keep in mind that there are several different types of identification methods, each with their own advantages and limitations. Since every natural product is different, each requires specific test methods to optimally identify the species and plant part. Due to this, manufacturers and suppliers need to collaborate with one another to determine the correct test methods to be utilized for each ingredient.

As to training of production/QA/QC personnel, when it comes to quality this contributing factor is often not top of mind for most people but it is actually the most important. The facility is only as good as the auditor that visits it. The testing equipment is only as good as the technician that handles it. Knowledgeable employees at every point of the organization is necessary—from the buyer who is capable of mentoring vendors to the quality department that consists of botanists, chemists, and microbiologists to the sales representative who can automatically distinguish if their client’s specifications are feasible. Not only do employees need to be knowledgeable in their trade, but they also need to understand and live by the quality policy of the company.

Atwater: There is no shortage of auditing services available to manufacturers of food/dietary ingredients/finished products. USP recently launched a Quality Systems GMP Audited Certification Program for dietary ingredient and supplement manufacturers. USP’s GMP facility audit program provides assurance that manufacturers not only meet FDA cGMPs, they exceed them. That’s because USP’s GMP audit program is the only program that requires manufacturers to comply with both FDA and USP GMPs. USP’s GMP audit program complements USP’s product-focused verification program and can serve as a stepping-stone for manufacturers toward achieving USP’s acclaimed dietary supplement USP Verified Seal.

With regard to testing, USP standards should be used more widely by the industry. Numerous FDA-conducted GMP inspections found that private specification set by manufacturers are often insufficient to ensure adequate quality of dietary ingredients and supplements. USP is recognized for the science-based quality standards it establishes for medicines and foods. USP quality standards include specifications for ingredients and finished products that list the tests and test procedures that need to be performed, and acceptance criteria for the results of the tests. Tests are performed for an article’s identification, for purity or content, for levels of potential impurities or contaminants, and for performance (e.g., finished product disintegration or dissolution). Wider use of USP standards, in conjunction with GMP compliance, can help ensure quality and consistency of dietary supplements as they do for medicines.

USP also provides training opportunities for QA/QC personnel through its Pharmacopeial Education (PE) program offerings. USP PE training programs are focused on quality control operations in a GMP setting and cover topics such as setting specifications for ingredients and finished products, test method validation and verification, and laboratory controls and auditing.

NIE: Full disclosure and transparency have become more important in the weight-loss/sports-nutrition area. What needs to be done to improve things?

Davis: The weight loss/sports nutrition market is rapidly expanding beyond the niche elite athletes to active nutrition consumers—you know, weekend warriors, fitness enthusiasts, and general aging population looking to live longer, better and wiser. These users–just like other supplement users—are seeking clean label products and are consequently scrutinizing the products offered in this category more than ever.

Pontiakos: The weight loss/sport-nutrition area can improve things in both the back end and front end. In the front end, manufacturers need to make sure their claims are accurate and true, not exaggerated. In the back end, weight loss/sports-nutrition companies should be extra rigorous when screening weight loss/sports-nutrition ingredients since they are more at risk for adulteration compared to most other areas. Remember, a manufacturer should question if a supplier has a price point well below the market price. For those in the sports nutrition segment, you can go even further and get your product NSF Sport Certified. NSF International created this certification program to “minimize the risk that a dietary supplement or sports nutrition product contains banned substances.”

Atwater: Stronger adoption of USP’s science-based public quality standards by the industry or in the regulations would provide a solution to this issue. However, for many weight-loss/sport-nutrition products, new public quality standards need to be developed. USP can develop the necessary science-based quality standards for weight-loss/sports-nutrition supplements, and does so following an open and transparent public consultation process, whereby input from manufacturers, regulators, suppliers, and any other interested party is considered and evaluated by volunteer experts organized in expert committees. USP is beginning to develop quality standards for sports-nutrition supplements and welcomes input from all interested parties. NIE

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