Romeo. “Your Plantain leaf is excellent for that.”

Benvolio. “For what, I pray thee?”

Romeo. “For your broken shin.”

— Romeo and Juliet, act I, scene II

Thus the lowly plantain (Plantago spp., Plantaginaceae) became a featured player in one of the most famous and beloved pieces of English literature. Being a man of his times (late 16^th-early 17^th century), William Shakespeare made numerous references to herbs in his work. In addition to the mention of plantain in Loves Labors Lost (act III, scene I), Troilus and Cressida (act III, scene XX), and The Two Noble Kinsmen (act I, scene II), there are references to roses (Rosa spp., Rosaceae) in Romeo and Juliet. And, in Hamlet, Ophelia presents to various characters rosemary (Rosmarinus officinalis, Lamiaceae), pansies (Viola tricolor, Violaceae), fennel (Foeniculum vulgare, Apiaceae), columbines (Aquilegia vulgaris, Ranunculaceae), rue (Ruta graveolens, Rutaceae), daisies (Bellis perennis, Asteraceae), and violets (Viola odorata, Violaceae). In fact, the Bard referred to so many plants in his works that “Shakespeare Gardens” dot the English-speaking world. A list of Shakespeare Gardens is provided by Wikipedia.¹ Shakespeare, of course, was not writing in an information vacuum. The plants to which he refers were all in common use at the time, and all can be found in more or less contemporary published herbals.

Nicholas Culpeper’s Herbal is both famous and fairly typical of Western herbal treatises. The entry for plantain begins with a simple physical description of the plant’s appearance and goes on to speak about where it might be found and for what it should be used. Not surprisingly his The English Physician was first published in 1652, The Complete Herbal in 1653, and no laboratory tests are mentioned.²

The structure of pharmacopeias* as they evolved was similar to that of the herbals, adding sections on standards of strength and purity to the descriptions of the properties, actions, uses, and dosages found in the earlier tomes. For instance, the first edition of the United States Pharmacopeia’s (1820)³ entry for plantain was quite brief, and Culpeper himself could have written the plant’s description.

The co-evolution of the herbal and the pharmacopeia seems to have been spurred by several historical trends. The first was the diligent application of the scientific method and the attendant explosion of knowledge about the world. Author and photographer Steven Foster discussed the second trend in his HerbalGram article about historical adulteration.⁴ Meanwhile, as commerce grew and new processing methods for materials (medicines, as well as everything else) became available, incentives and opportunities to cheat also increased. Advances in science and technology provided the twin benefit of being able to better identify and test superior material and to detect cheats. The 1918 United States Dispensatory (USD, 20^th edition)⁵ entry for plantain provided descriptive information on the herb as well as a few newly identified organic chemicals. The Plantain Leaf monograph had been eliminated from the USD by the time the 25^th edition was published in 1955,⁶ but Bisset and Wichtl’s Herbal Drugs and Phytopharmaceuticals (2001 edition)⁷ provided an authoritative treatise on plantain leaf that incorporated standards from the Austrian Pharmacopoeia, the Pharmacopoeia Helvetica (Switzerland), and the German Pharmacopoeia. In addition to the physical description of the plant (accompanied by color photographs), Bisset and Wichtl’s plantain monograph includes additional specifications and tests that require laboratory facilities.

>For better or for worse, many of the simple, unprocessed, and easily identifiable herbs of a bygone era can be found in retail commerce only rarely and with some degree of difficulty. Many modern botanical products intended for health-related purposes are, for the most part, quite complicated, often requiring additional testing for authentication of identity and for the presence of accidental or intentional adulterants, including contaminants such as heavy metals, pesticides, noxious microbes, and mycotoxins.

As knowledge on the composition and properties of herbs has evolved, so too has the ability to evaluate those properties (e.g., marker compounds) using technology. The modern world also superimposes itself on commerce in the form of smelters, internal combustion engines, fecal coliforms, leaded gasoline, pesticides, prescription drugs, and other noxious substances that necessitate testing in addition to evaluating the inherent properties of the raw materials and finished products. No evaluation of herbal quality would be complete without some means of assuring that these and other unintentional contaminants are absent.

In addition to an individual manufacturer’s desire to create and sell only the highest quality products, there are significant regulatory requirements surrounding the sale of botanical goods. Whether they are called natural health products (Canada), therapeutic goods (Australia), dietary supplements (United States), or phytomedicines (Europe), there are regulatory requirements to set specifications and to test for conformity with those specifications. Thus, the laboratory enters the scene.

Role of Contract Analytical Labs

In the United States, at least, manufacturers are not required to have a laboratory as part of their dietary supplement operations. They are, however, required to have both raw material and finished product specifications, and to have a means to demonstrate that those specifications are met, i.e., analytical tests. Many companies rely on independent commercial analytical laboratories to perform this required testing on a contractual basis — these are referred to as contract labs.

Contract analytical laboratories provide an extensive range of services and can be a cost-effective way to test the quality of raw materials and finished products. Whether to assist in guiding purchasing decisions, developing or verifying claim and labeling information, or performing routine quality control duties, the decision to identify and hire a laboratory partner generally begins with the identification of the company’s needs.^† From routine testing for compliance with current Good Manufacturing Practices (cGMPs) to testing in support of a company-sponsored clinical trial, it is imperative that the company clearly knows its requirements and compares those needs to a laboratory’s capabilities.

Many laboratories offer an impressive suite of testing services, but every laboratory has different areas of expertise and competency. So rather than deciding whether or not “one-stop shopping” is best suited for a particular manufacturer’s needs, the company should independently evaluate each laboratory service. With dietary supplement testing, very little is really “routine,” and the quality of contracted work can vary significantly. Further, many laboratories that offer numerous contract testing services subcontract some of those tests to other laboratories, and it is important for manufacturers to know whether the laboratory work is being done in-house or sent out.

The complexity and variety of finished products, coupled with the freedom to change a formulation at will, result in a constant challenge for analytical laboratories. The majority of single-component dietary supplement products may be described as generic, but they are not necessarily identical, and any analytical method used on a given product should be valid for its intended use for that product. Multi-component products are neither generic nor identical, so assuring suitability for intended use is even more important. The US dietary supplement cGMP regulations require that testing be performed using methods that are “scientifically valid.” Although the rule fails to define the term, there is considerable agreement on its meaning within the scientific literature (see Betz et al. Fitoterapia. 2011;82:44-52⁸).

Questions of Accreditation

When evaluating contract laboratories, potential customers should seek documentation from the lab in the form of third-party accreditation of their operations to ensure the quality of the lab’s measurements. Customers must ask not only if the lab has appropriate accreditation, but also if the accreditation’s scope covers the contract analysis they wish to purchase. Unfortunately, there are no specific regulations that provide federal government oversight of the behavior of contract laboratories that service the supplement industry, so buyers of laboratory services must exercise considerable diligence and good judgment. In addition, regulators can hold accountable contract laboratories performing testing services that are part of a GMP-related process. A qualified contract laboratory should have a written standard operating procedure (SOP) that will define the GMP term “scientifically valid.” When selecting and qualifying a contract laboratory, customers should ask for a copy of this SOP, as it will provide a great deal of information on the laboratory’s position on the matter.

Selecting and qualifying a contract laboratory can be an important business decision for a manufacturer, one that should not be underestimated, as contract laboratories that perform analytical services can have an impact on meeting minimum GMP requirements. Experience has led to the identification of several easy-to-spot warning signs about laboratories-for-hire and several more signs that are not so easy to recognize. For instance, manufacturers should be wary of laboratories that claim to be certified by the US Food and Drug Administration (FDA). Contrary to some contract laboratory marketing materials and websites, there is no such thing as an “FDA-approved” or “FDA-certified” laboratory. A laboratory that makes such claims either does not understand the regulatory environment in which it operates or perhaps it may be actively deceiving potential clients. The FDA can inspect a laboratory, but the result of an inspection is not “certification” or “accreditation;” it is merely a clean inspection. All FDA inspections result in the generation of an inspection report, so if a laboratory that has been inspected is chosen by a company, that company should request the FDA inspection report, when available, to determine if the inspected laboratory’s operations are relevant to the analyses needed, whether or not significant deficiencies were found by FDA, and if such deficiencies have been corrected by the laboratory. Laboratories might be certified or accredited by the US Environmental Protection Agency under various state programs, but few, if any, of these programs are directly related to dietary supplement analytical endpoints. Complicating this picture even more, some laboratories advertise with the term “FDA-registered.” There is a “registration” process at the FDA for contract laboratories, but it is just that: a registration process that does not involve approval, certification, accreditation, or even inspection by FDA. Claims by laboratories that they are “FDA-registered” do not mean anything from a laboratory performance perspective.

Asking for certification or accreditation information provides pieces to a puzzle that helps customers decide if the lab meets their needs and expectations. As such, the answer is just one data point among many that can help the customer make a choice. There are different types of certifications, from the International Standards Organization (ISO) and others. Simply having an ISO certificate laying around the lab means little if it is the wrong ISO certificate. Some ISO certifications are for business practices, others for general laboratory competence. The most rigorous ISO certification requires SOPs and extensive documentation for each laboratory method. And even with that, it is possible to get one of the higher-level accreditations and have some individual methods included within the scope of the acreditation and others (without SOPs, etc.) not within the scope. Customers must ask not only whether or not the lab has an accreditation, but also whether or not the contract analysis they wish to purchase is within the scope of that accreditation. The nature of the dietary supplement testing business, with the constant need to tweak methods for new matrices, makes it impractical for many contract labs to become accredited to the higher standard. The lower standard is reasonably generic, and a lab may decide it is too generic to mean anything. However, achieving the lower standard does demonstrate awareness by the lab that laboratory quality programs exist and a willingness to invest in having someone come in and have a look around. A customer who makes a purchasing decision based solely on presence/absence of an accreditation is asking someone else (the accreditor) to do his or her due diligence for them. Customers can and should ask the lab for as much information as is necessary to make them comfortable with the laboratory’s competence.

Good Laboratory Practices (GLPs) is a term with limited scope that applies to animal, drug, and environmental testing. GLPs are designed for studies in which a director is involved (e.g., a clinical trial or animal study) and not for routine analysis. Laboratories that use GLPs as a selling point for routine testing services may either actively be prevaricating or possibly ignorant of the scope of such claims. That being said, if the careful documentation and controls required to maintain GLP-compliance are translated through to all the laboratory services, there could be a distinct advantage to contracting with a GLP-compliant laboratory. In sum, a lab can state that it performs studies according to GLPs in addition to routine analysis of dietary supplements.

There is one type of accreditation that may be of interest when considering whether or not to hire a contract laboratory. Documentary laboratory standards are produced and published by the ISO, and compliance with these standards is evaluated by third-party inspectors, not by ISO. There are several levels of ISO accreditation that range from low-end compliance with general quality management principles to highly detailed laboratory and method-specific programs, so manufacturers should determine the level of ISO accreditation claimed by the laboratory before entering into a contract. The main standard used by testing and calibration laboratories, ISO 17025, applies to overall laboratory operations as well as to individual methods of analysis conducted within the laboratory, so a dietary supplement manufacturing company must determine which methods are included in the accreditation. Analyses performed using a method that falls outside of the accreditation would not be considered ISO 17025 compliant.

Regulatory Context

According to the US dietary supplement cGMP regulations (21 CFR Part 111), manufacturers must identify every point in the manufacturing process that may require control and mandates that every step of the manufacturing, packaging, labeling, and holding process for dietary supplements must have specifications, and that all steps taken during manufacture be documented. GMPs are fundamentally about traceability in product manufacturing and rely heavily on documentation. In a laboratory, this translates to having SOPs for all operations, including laboratory test methods.

In choosing a laboratory, a company must ensure that the lab’s operations, with respect to testing the company’s raw materials and/or finished products, are in compliance with cGMPs. The FDA expects that laboratory work performed in the course of a product’s manufacture, whether in-house or by a contracted laboratory, meets all the dietary supplement cGMP requirements. In some ways, the cGMPs appear vague and not particularly informative (i.e., prescriptive) on this subject; that is because FDA has provided considerable latitude to companies in establishing their specifications and testing protocols. Evidence must be provided that the laboratory examination and testing methodologies are “appropriate for their intended use” (21 CFR 111.320(a)) and that methods used to determine whether or not specifications are met are “appropriate and scientifically valid” (21 CFR 111.75 (h)(1)).^9,10

Proof that these requirements are met requires data, collected by the laboratory, on each individual lot of each raw material or finished product. Because the cGMPs state that the burden is on the manufacturer to document that these requirements are met, a close working relationship with the contracted laboratory is highly recommended. According to an industry source,¹¹ in January 2012, FDA reaffirmed its intention to begin Section 111 GMP inspections of contract analytical laboratories. Contract laboratories are seen by FDA as an extension of the manufacturer and are thus within the scope of a Section 111 inspection. In general, contract labs have been at arms-length with FDA inspectors on the GMP front, having focused on paperwork rather than physical lab inspections to verify lab performance. The consequences of a decision by FDA to inspect the labs themselves, whether in-house or contract, are potentially far-reaching for both laboratories and manufacturers. It is important to understand that there are not universal testing methods that work for a given marker in a wide range of different sample matrices. For example, a method developed and validated on a standardized botanical extract may not work properly for that same extract in a tablet that also contains 15 other ingredients. Therefore, a great deal of modification to any method is often needed to obtain valid data on a sample matrix that might vary from the original method. Some laboratories perform additional quality control (QC) measures, such as measuring replicates and spikes on a novel matrix to assure that they have some basis for defending the data, while others do not. These are the types of hidden value-added benefits that separate one lab from another, and usually will explain why one lab is charging a higher fee for what might appear to be the same service.

Choosing a Laboratory for Routine Analytical Testing of Dietary Ingredients and Finished Dietary Supplements

When choosing a contract lab, the first question should be this: Are the methods to be used by the contracted laboratory on a company’s test articles compatible with its specifications? For example, if a vitamin manufacturer is seeking microbiological assay, an experienced food laboratory may not be of much use unless that laboratory can demonstrate experience with the company’s product matrix, or at least related matrices (e.g., how the products are actually formulated — what types of materials are included in the production of the supplement, including tablet coatings, excipients, and other materials that can affect the ability to conduct an accurate analysis of targeted dietary ingredients and/or marker compounds). If the company has become comfortable with the concept of “off-the-shelf” testing on a one-off basis and shops for laboratories by price and/or turnaround time as the primary criteria for choosing a contract lab, the company may be in for a surprise when an FDA inspector stops by and wants to see the documentation related to work conducted by the contracted laboratory.

The FDA will expect SOPs for testing and for making the determination that the tests are both scientifically valid and appropriate to the company’s test articles. Inspectors also will expect the company’s sampling plan, calibration, data, and justification for reference material selection, etc., to be readily available. Each time a manufacturer begins a relationship with a new contract laboratory or changes one or more of its formulations, that manufacturer should require verification or validation of method performance on its materials and expect to pay for this additional information. Ultimately, jumping from laboratory to laboratory may be a false economy.

FDA always has had the authority to ask a company for evidence that its contract lab is in compliance with cGMPs. If the agency starts inspecting these labs and reviewing their SOPs and records, a contracting dietary supplement manufacturer could have a problem if it has not done its homework by qualifying, auditing, and inspecting the laboratories it is using. Any company using contract laboratories should be sure that those laboratories are willing to support the company should it be inspected by FDA by providing the company and/or FDA with the supporting documentation or data requested. A situation in which a contract laboratory is unwilling to share supporting documentation or data that the lab deems “proprietary” should be viewed by the customer company as a big red flag. One of the biggest potential hazards is not poor analytical method selection or even incomplete record keeping; it is outsourcing analytical laboratory work to a so-called “dry lab.” To be clear, the term “dry lab” is being applied in this context as described in Wikipedia^‡: “…supplying fictional (yet plausible) results in lieu of performing an assigned experiment.”¹² The development of pharmacopeias over the past 500 years and the mere existence of advanced testing procedures are not evidence of compliance; there must be actual records, i.e., documentation that demonstrates the samples were tested and the specifications were met.

Dry-labbing is a phenomenon that has been in existence for some time now, but had not really caught the attention of the supplement industry until a televised report by Dateline NBC (Season 20, Episode 29, March 18, 2012) exposed the practice to a wider audience. The dry lab story starts when the manufacturer sends a sample and a sample submission form to a contract laboratory. In most dry lab cases, the lab will request detailed information about the sample, including a range of expected results. Because legitimate labs may also request this information as a way to ensure that the methods employed will be valid for the sample type and to allow for accurate sample preparation, these questions alone should not be cause for suspicion. Nevertheless, when the dry lab receives the sample, it is not actually tested or an inexpensive generic analytical method is employed that yields no real useable data. The lab then generates a report that essentially affirms the expected result as provided by the customer.

While it has been suggested that challenging laboratories with “dummy samples” is a way to spot a dry lab, this is not the recommended approach for developing a relationship with a prospective contract lab (see sidebar “Seven Basic Tips for Selecting a Contract Laboratory” on page 56). Certainly, dummy samples could expose a dry lab, but companies can take less extreme actions to protect themselves. First, a company should take time and care in choosing the contract laboratory and never “lab shop” or buy services based solely on price. While spending an appreciable amount of money does not guarantee results, one can be fairly certain that if a lab is charging far less then most competitors, there is a reason. (More guidance on selecting a contract analytical lab can be accessed in the Nutraceuticals World archives for Dr. Brown’s Quality Focus column, titled “Outside Analytical Labs,” published in 2009.)¹³

It is recommended that site visits, paper audits, and even physical audits of a contract laboratory be conducted on a regular basis by the contracting company. The company should inquire about the lab’s experience in the type of testing being sent to them, including questions on participation in any industry initiatives, such as the Dietary Supplement Quality Assurance Program managed by the National Institute of Standards and Technology (NIST). An audit should include the review of general and method-specific SOPs, staff education and training, method citations, date-stamped raw data, and analytical testing reports. Certificates of analysis for reference materials and purchase orders for reagents, chromatographic columns, and calibration standards should be reviewed. A contract lab should be able to walk their client through sample tracking procedures, including sample and equipment logs, laboratory notebooks, and the sample holding room. Instrument equipment logs also can be very telling: They should include details of instrument usage and maintenance. All of the information noted above, and more, is required for compliance with the GMP rule in the United States. If the laboratory refuses to show any of it, the manufacturer has no way to assure an FDA inspector that it is in compliance during a GMP inspection. Nonetheless, the manufacturer’s QC director should keep in mind that if the laboratory is testing multiple samples from different clients at the same time, the laboratory is responsible for protecting client confidentiality and, therefore, may rightfully show auditors only the records applicable to the testing being audited.

Certificates of Analysis and Analytical Test Reports

Company quality control personnel should pay close attention to the analytical test reports or certificates of analysis from contract laboratories, as warning signs are often found in such documents. Quality assurance personnel should be both qualified and prepared to evaluate carefully all available documentation. For example, unlabeled and undated chromatograms with no unique identifiers, such as the company’s product or material lot number and the date of analysis, can be recycled over and over again both for the contracting company’s samples and those of other clients of the laboratory. The manufacturer’s quality assurance team also can request to see chromatograms for their ingredients in different products that it manufactures. If the chromatograms look eerily similar, they might just be the same chromatogram. Photocopying an old chromatogram is obviously lower cost than buying and running a device that analyzes high-performance liquid chromatography (HPLC) and does not require technically trained operators. It is also important to keep in mind that chromatography raw data often results in a lot of questions and confusion; if the party reviewing the data is not familiar with the test or the protocol, the data alone can be meaningless. This can drive up the cost of testing because expert time is needed to explain data, yet many companies do not want to pay more for that level of service.

Telltale clues that a contract analytical laboratory is dry-labbing also can be found in the analytical test reports. The following is a list of red flags:

Analytical results reports that refer to modified official methods or modified USP (United States Pharmacopeia) methods but do not provide details on the modifications or data to support the validity and fitness for the purpose of the modified methods.

Citations of methods from peer-reviewed scientific journals that are used to measure something “in urine” or “in serum,” but not in a dietary supplement matrix. This is especially true if the detector in the paper is a refractive index (RI) detector and the lab uses a UV detector. However, many old RI methods are now done using evaporative light scattering detectors (ELSD) or mass spectrometry detectors, so this alone is not proof of dry-labbing. Also related to this problem are references to very obscure journals for methods that are available in commonly utilized journals. This was observed in many dry lab situations in the past. Having to spend an enormous amount of time to find the citation often is a way to create ambiguity.

Incompatibility between the equipment and/or detector employed by the contract lab when compared to that reported in the journal-cited method. For example, peaks generated by a chromatographic separation achieved using gradient HPLC will not be quantifiable if the HPLC column is coupled to an RI detector.

The order of magnitude for the measurement being taken is different than that of the published test method — for example, using a method designed to test the purity of a 100% pure compound for measuring trace amounts of the compound in a complex matrix, or vice versa. Again, if data are reported in the analytical range expected in a matrix and the method is incapable of separating the analyte from matrix peaks or if the matrix findings are below the LOD/LOQ (the limit of detection and the limit of quantification) of the published method, then the report can be deemed fraudulent. In such a case (as with the “urine” or “serum” example), the burden of proof would be on the lab to prove that the method was capable of achieving the desired results. A simple citation on a certificate of analysis would not suffice. It should be noted that many of these clues also can serve as indicators that the lab is simply not using valid analytical methods even if it is actually performing the tests.

Finally, additional warning signs also can include the lab’s refusal to produce copies of a lab notebook, its refusal to complete a lab audit questionnaire for the client, and its refusal to produce chromatograms or raw data for analysis (when appropriate).

The contract laboratory is essentially an extension of the manufacturer. Contract labs often must modify methods, whether to adapt to new technology or to expand the scope and applicability of an existing method. This is not unusual, but when a method has been modified, the contracting company should insist it is privy to the details of the modification, the method re-validation or verification SOP, and the data that prove to the client company (and FDA) that the method remains scientifically valid and suitable for its intended use. That method suitability must extend to the company’s product type. Verbal or written assurances of such procedures are not sufficient; there must be adequate documentation. Anything else can put the client company at risk. The manufacturer should expect to pay for the extra services incurred in demonstrating method performance

The process of ensuring that a method is “fit for purpose,” or, in other words, is appropriate for its intended use, is generally demonstrable with some relatively simple experiments. The process of performing the experiments necessary to demonstrate that a method is scientifically valid is called a validation study, and both are fundamental requirements for method use in the dietary supplement cGMPs environment. There are internationally recognized definitions and guidelines for demonstrating method performance.^14,15

As more methods and reference materials become available, and as the dietary supplement industry becomes more accustomed to requesting that laboratories demonstrate that their methods are appropriate for their intended use, contract testing of dietary supplements will evolve. It should be remembered that sample matrices detailed in compendia protocols and tested using those protocols do not have to be validated in the laboratory again, but the lab does have to demonstrate proficiency in using the method. This can be done using spikes, calibrations, duplicates, etc. 

If the ingredient supplier or finished-product manufacturer has a qualified in-house scientist, that person should review the analytical test reports. If not, the company should contract with a qualified expert to review the reports. If a method citation looks like unintelligible gibberish, there is a fair chance that some obfuscation is occurring. More information on what should be contained in an analytical test report or certificate of analysis can be found in the Nutraceutical World article, “Certificates of Analysis,” published in November 2008.¹⁶

A reliable and responsibly run contract lab should be willing to share information, and a contract laboratory must always provide copies of raw data upon request. A laboratory may choose to treat its in-house methods as intellectual property and may choose not to release copies of the methods, but methods must be made available for review during an inspection. If they are not made available for review, it is possible that they do not exist. All competent quality control managers should “think GMP” when considering their off-site operations, i.e., outside contract laboratories. Manufacturers should be wary of laboratories that are unwilling to allow an on-site visit or audit. Manufacturer QC personnel should be aware that inspections are disruptive and the schedule of the laboratory and availability of key staff should be considered.

Paula N. Brown, PhD, is a natural product chemist and the director of the British Columbia Institute of Technology’s Natural Health and Food Products Research Group. She has been supporting the Canadian natural health products and the US dietary supplement industries for more than a decade through applied research activities including product development, establishment of quality standards, and regulatory compliance. She is actively involved with numerous nonprofit organizations, including AOAC International, and is a member of the ABC Advisory Board. She also has written the “Quality Focus” column for Nutraceuticals World, an industry trade publication.

Joseph M. Betz, PhD, received his doctorate in pharmacognosy from the Philadelphia College of Pharmacy and Science. He worked at the US Food and Drug Administration’s Center for Food Safety and Applied Nutrition for 12 years, was vice-president of science and technical affairs at the American Herbal Products Association for two years, and has worked at the US National Institutes of Health since 2001. Dr. Betz is the recipient of the American Botanical Council’s first Norman R. Farnsworth Award for Excellence in Botanical Research and the American Society of Pharmacognosy’s Varro E. Tyler Prize for outstanding scientific contributions to the field of dietary supplements, with special emphasis on botanicals. He is a long-time member of the ABC Advisory Board.

Frank L. Jaksch, Jr., co-founded ChromaDex^®, Inc. in 1999 and serves as chief executive officer. Under his leadership, ChromaDex has focused on developing a comprehensive natural products chemistry business, expanded into international markets, and built a roster of Fortune 500 customers. ChromaDex is now a leading supplier of botanical reference standards and phytochemical products, analytical services, and novel ingredients to the dietary supplements, sports nutrition, food and beverage, cosmetic, and pharmaceutical markets. He is a member of ABC’s Director’s Circle.

* Editor’s note: ABC prefers to use the spelling pharmacopeia without the second “o” in the diphthong, as is customarily the modern spelling, using the more archaic pharmacopoeia for those publications and/or organizations that still choose to use it, e.g., the American Herbal Pharmacopoeia, the European Pharmacopoeia, etc.

^† This article is written primarily with respect to commercial companies that are purchasing botanical (and other) raw materials as ingredients for use in dietary supplements. However, the information in this article also can be relevant to the purchase of raw materials for use in herbal teas — often regulated as conventional foods in the United States, depending on how the teas are labeled, and thus not subject to the same level of stringency required by GMPs for dietary supplements. Also, many of these issues apply to the purchase of botanical materials for use in cosmetic products. Further, there are times when researchers of a clinical trial on an herbal dietary supplement will choose, or be required, to have the test material analyzed for identity and/or potential contaminants by a contract laboratory; in such cases, many of these issues and guidelines will apply.

^‡ The use of Wikipedia to define “dry lab” is provided because this term is relatively new that it has not gotten into common parlance, except insofar as it is recently generated jargon within the herb, dietary supplement, and analytical laboratory communities in the United States (http://en.wikipedia.org/wiki/Dry_lab; accessed July 25, 2013).

References

1. Shakespeare garden. Available at: http://en.wikipedia.org/wiki/Shakespeare_garden. Accessed December 24, 2012.
2. Culpeper N. The English Physician: Or the Astro-Physical Discourse of the Vulgar Herbs of This Nation. London: Peter Cole; 1652.
3. Medical Societies and Colleges. The Pharmacopoeia of the United States of America. Boston, MA: Wells and Lilly; 1820.
4. Foster S. A brief history of adulteration of herbs, spices, and botanical drugs. HerbalGram. 2011;92:42-57.
5. Remington JP, Woods HC. The Dispensatory of the United States of America. 20th ed. Philadelphia: JB Lippincott & Co.; 1918.
6. Osol A, Farrar GE. The Dispensatory of the United States of America. 25th ed. Philadelphia: JB Lippincott & Co.; 1955.
7. Bisset NG, Wichtl M (eds). Herbal Drugs and Phytopharmaceuticals — A Handbook for Practice on a Scientific Basis With Reference to German Commission E Monographs. 2nd ed. CRC Press; 2001.
8. Betz JM, Brown PN, Roman MC. Accuracy, precision, and reliability of chemical measurements in natural products research. Fitoterapia. 2011;82:44-52.
9. Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements. US Code of Federal Regulations, Title 21, Volume 2, Section 111.320(a): What requirements apply to laboratory methods for testing and examination? Revised April 1, 2013. Available at: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=111&showFR=1. Accessed July 21, 2013.
10. Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements. Requirement to Establish a Production and Process Control System. US Code of Federal Regulations, Title 21, Volume 2, Subpart E; Section 111.75 (h)(1). Available at: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=111.75. Accessed July 21, 2013.
11. Czap A. Editorial — Atlas Shrugged (Kind of). Altern Med Rev. 2012;17:1-4. Available at: www.altmedrev.com/publications/17/1/1.pdf.
12. Dry Lab. http://en.wikipedia.org/wiki/Dry_lab. Accessed July 21, 2013. Accessed June 25, 2013.
13. Brown PN, Dentali S. Quality focus: outside analytical labs. Nutraceuticals World. January 2009;12(1):32-34. Available at: www.nutraceuticalsworld.com/issues/2009-01/view_columns/quality-focus-outside-analytical-labs/. Accessed January 16, 2013.
14. Horwitz W. Protocol for the design, conduct and interpretation of method-performance studies (technical report). Pure & Applied Chem. 1995;67:331-343.
15. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartate Guideline — Validation of Analytical Procedures: Text and Methodology, vol. Q2, (R1). Available at: www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4/Q2_R1__Guideline.pdf. Accessed February 28, 2013.
16. Brown PN. Certificates of analysis. Nutraceuticals World. November 2008; 11(10):32-33. Available at: www.nutraceuticalsworld.com/issues/2008-11/view_columns/quality-focus-certificates-of-analysis/. Accessed January 16, 2013.
17. Dietary Supplement Analysis Quality Assurance Program. Available at: www.nist.gov/mml/csd/organic/dsqap.cfm. Accessed January15, 2013.
18. British Columbia Institute of Technology. Available at: www.bcit.ca/appliedresearch/nrg. Accessed January 15, 2013.