06/25/99 Draft Report of the
FOOD ADVISORY COMMITTEE
DIETARY SUPPLEMENT WORKING GROUP
On
INGREDIENT IDENTITY TESTING
RECORDS AND RETENTION
PREFACE
Current Good Manufacturing Practices (GMP) guidance is needed to assist a firm in selecting the appropriate tests to identify dietary supplement ingredients. Section 402(g)(2) of the Federal Food, Drug, and Cosmetic Act (the act) states that GMP regulations may not impose standards for which there are no current and generally available analytical methodologies. Analytical methodologies are available for identification of some dietary supplements such as vitamins and minerals, but a comprehensive compendium of generally available scientifically validated tests for identification of dietary ingredients has not been compiled. In particular, valid analytical methodologies are not available for many dietary ingredients, for example, botanicals and biologicals such as blood products, organ tissue, cartilage, and etc.
Morphological characters and organoleptic characteristics are used in some cases to validate the identity of botanical ingredients at the time of collection or for unprocessed botanicals. When sufficient morphological characters are present to separate the plant species from other plant species, then an accurate identification can be made since morphological characters are the sole basis of distinguishing most of the world's plant species. However, unprocessed botanicals that do not contain all the plant parts necessary to include adequate morphological characters to assure the correct species should have other identity aids or tests to assure the identity of the botanical. Greater detail on botanical ingredient identification is presented in the outline that follows.
Confirming dietary supplement ingredient identity and safety of animal origin products employ specific technical analytical and record keeping approaches. It is possible that confirming identity and safety of biological ingredients may involve a combination of analyses designed to determine the presence of animal and plant matter and to differentiate family/species and tissue. Records and reports are needed to assure that products that are manufactured with bovine-derived materials at foreign sites or by foreign manufactures are free of disease and follow appropriate USDA regulations and that products that are manufactured with fish and fishery product materials follow appropriate FDA HACCP regulations. More detailed information on these issues follows in the Report outline.
The misidentification of dietary ingredients used in dietary supplements can present significant public health and economic concerns. GMP guidance is needed to assist a firm in following quality control and other written procedures, such as record keeping, necessary to ensure that dietary supplements are produced under conditions that will result in a safe and properly labeled product. Written procedures for manufacturing processes (e.g., master production and control records and batch production and control records) are necessary to ensure that good manufacturing procedures can be followed on a day-to-day basis. The written procedures are the standard-based criteria for evaluating day-to-day manufacturing operations. Data records from the day-to-day operations and evaluations are used to ensure that the dietary supplement products have the identity, purity, and strength they are represented to posses. Additionally, written procedures for handling complaints and records of reported complaints involving illnesses and injuries regarding dietary supplements are useful in periodic trend analyses to determine whether a reported injury or illness constitutes a serious public health problem.
The Center for Food Safety and Applied Nutrition (CFSAN), FDA asked its Food Advisory Committee (FAC) to form a GMP Working Group to consider two topics: 1) dietary supplements ingredient identity testing and 2) records and retention.
The GMP Working Group addressed the following FDA charges to the FAC:
Dietary Supplements GMP/Adequate Testing for Identity of Ingredients: The Working Group was asked to consider what constitutes "adequate testing" for identity of different dietary ingredients used in dietary supplements. What is needed to identify or provide assurance of the identity of a dietary ingredient, both when analytical tests are generally available and when analytical methods are not generally available? The Working Group outline
Identifies the principles and questions a manufacturer would need to consider when selecting or designing a process to ensure the identity of a dietary ingredient. The criteria addresses
a) The nature of the ingredient (e.g., a vitamin, mineral, amino acid, herb or botanical, or other dietary supplement ingredient);
b) The form of the ingredient (e.g., whole botanical, powder, or extract); and
c) Special contents of the ingredient if relevant to the ingredient's identity (i.e., level of a chemical(s), such as a marker compound, in the botanical ingredient to distinguish the special contents of the botanical ingredient from other botanical ingredients from the same species of plant).
Includes citations to reference sources or compendia of available identity tests for botanical characters, molecular biological assays, chemical content and physical forms.
Identifies factors to be considered in development of a new method for providing the assurance of the identity of a dietary ingredient.
Includes criteria a dietary supplement manufacturer should use to determine if a particular identity test is the most appropriate method of providing assurance of the identity of a dietary ingredient.
Includes scientific or technical criteria a dietary supplement manufacturer should consider when determining if
a) Botanical characteristics, including morphological, anatomical, and/or organoleptic characteristics of the ingredient are sufficient and therefore the most appropriate means of providing assurance of the identity of a dietary ingredient;
b) A Certificate of Analysis (CofA) is the most appropriate method of providing assurance of the identity of a dietary ingredient; and
c) A microscopic and/or chemical test is the most appropriate method of providing assurance of the identity of a dietary ingredient.
Dietary Supplements GMP/Records and Retention: The Working Group was asked to consider what records are necessary to demonstrate that product safety is maintained throughout the manufacturing and distribution process, i.e., that dietary supplements have been produced under good manufacturing practices. The Working Group outline
Identifies records that are necessary to ensure that the identity, purity, composition, and quality of the dietary supplement will not adversely affect public health.
Identifies additional records that could assure dietary supplement manufacturers that GMPs are maintained throughout all their manufacturing, including safety controls in computer controlled/assisted operations and records of internal quality audits.
Identifies records that are needed to evaluate reports of injuries or illnesses associated with a product including production and distribution records (e.g., lot or batch numbers, distribution information, reserve samples) and records needed to facilitate product recall.
Dietary supplements are regulated under the Federal Food, Drug, and Cosmetic Act (the Act), as amended by the Dietary Supplement Health and Education Act of 1994 (DSHEA, P.L. 103-417). A dietary supplement means any ingested product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following ingredients: a vitamin; a mineral; an herb or other botanical; an amino acid; a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any ingredient described (see 201(ff) of the Act.)
Dietary supplements may not contain dietary ingredients that present a significant or unreasonable risk of illness or injury (see section 402(f) of the Act) or that may render the supplement injurious to health (see section 402(a)(1) of the Act). The manufacturer bears the responsibility for ensuring that its dietary supplement products are safe. The DSHEA amendments grant authority to the Secretary, as delegated to the FDA, to establish GMP regulations governing the preparation, packing, and holding of dietary supplements under conditions that ensure their safety (see section 402(f)(1) of the Act).
Purpose of the Working Group Report
The FAC/GMP Working Group includes membership from the FDA FAC as well as special liaisons from the dietary supplement industry. The Report includes the recommendations to the FDA via the FAC concerning GMPs for dietary supplements specific to ingredient identity testing and records/records retention.
This Report provides guidance in selecting the most appropriate and reliable test(s) for dietary supplement ingredients. In responding to the FAC charge relating to dietary supplement ingredient identity testing, this Report takes a narrow definition of ingredient identity testing, i.e., testing to establish the origin, nature, characteristics, form and taxonomic classification (where applicable) of dietary supplement ingredients as defined by statute. A broader definition of ingredient identity testing that would address microbial and chemical contamination is beyond the scope of the Working Group ingredient identity testing charge. Adulteration is an important issue and needs to be included in the full GMP regulation and related guidance to ensure the purity, composition, and quality of the dietary supplement. Principles used in selecting ingredient identity tests are also appropriate in selecting tests to detect adulteration; notation in this regard is included in the Report. The Working Group understands that FDA will address the issue of contaminants and adulteration within the full scope of GMP regulations.
This Report is not prescriptive; it does not recommend specific test procedures or acceptance criteria but provides general principles for consideration in the setting of performance standards for tests. Performance standards must be sufficiently accurate to distinguish or separate the ingredient from other ingredients that could adulterate or be confused with it. The goal of identity testing is to assure the public that what is on the product label is true and accurate. There are several steps in achieving this goal. One is confirming the ingredient identity provided by a supplier's certificate of analysis (CofA). It is possible that the CofA may or may not be complete. If the certificate is not complete, it is the obligation of the manufacturer to fill in the gaps and confirm the ingredient identity as well as to institute a quality assurance process to verify the reliability of the supplier's CofA. A firm can require suppliers to do tests in advance as part of supplier specifications, perform tests on site, or send a sample to a third-party laboratory for testing. All of these are elements of making sure the label is accurate. The testing performance standards should be based on a combination of vendor audits, ingredient specifications, and a sufficient number of identity tests conducted with the necessary frequency to insure that the product is actually what is stated on the label on a batch-to-batch basis. For final or finished products, the manufacturer needs to have a system that assures the identity of all the ingredients in the final product.
The Report also provides guidance in developing and maintaining records necessary to ensure that dietary supplements are produced under conditions that will result in a product that is not adulterated and is properly labeled. In responding to the FAC charge related to record keeping, all ingredient tests are addressed including ingredient identity, contamination, and adulteration. The record keeping section has been written to generally follow the format of the FDA Advanced Notice of Proposed Rulemaking for Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Dietary Supplements, of February 6, 1997. The general goal of record keeping from a public health perspective is to assure product safety by developing written procedures for manufacturing, documenting that the written procedures are followed on a day-to-day basis, and maintaining records for tracing the manufacturing process forward and backward when adverse events are associated with a product.
Food Advisory Committee Members, Consultants, and Liaisons
Bruce M. Chassy, Ph.D. -- CHAIR
Head, Department of Food Science
& Human Nutrition
University of Illinois at Urbana
905 S. Goodwin, 260 Bevier Hall
Urbana, IL 61801
(217) 244-4497
(217) 244-7877 FAX
B-Chassy@UIUC.Edu
Owen R. Fennema, Ph.D.
Professor
Department of Food Science
University of Wisconsin
1605 Linden Drive
Madison, WI 53706
(608) 263-2002
(608) 262-6872 FAX
OFennema@FacStaff.Wisc.Edu
Stephen H.Benedict, Ph.D.
Associate Professor
Department of Microbiology
7035 Haworth Hall
University of Kansas
Lawrence, KS 66045
(785) 864-4007
(785) 864-5294 FAX
Benedict@falcon.cc.ukans.edu
Susan K. Harlander, Ph.D.
Vice President, Green Giant R&D
The Pillsbury Company
330 University Avenue, SE, MS 9921
Minneapolis, MN 55414
(612) 330-8349
(612) 330-8288 FAX
Sharlander@Pillsbury.Com
Mary Y. Wang, Ph.D.
Senior Scientist
California Dept. of Health Services
Food & Drug Branch
714 P Street-MS 357
Sacramento, CA 94234-7320
(916) 322-7114
(916) 322-6326 FAX
MWang@FDB.DHS.CAhwNet.Gov
Edward M. Croom, Ph.D.
Assoc. Prof. Pharmacognosy
Research Institute of Pharmaceutical Services
School of Pharmacy
University of Mississippi
University, MS 38677
(662) 232-5941
(662) 232-7062FAX
EMCroom@OleMiss.Edu
Forouz Ertl, Ph.D.
Botanicals International
2550 El Presidio St.
Long Beach, CA 90810
(800) 247-7555, ext. 109
(310) 637-3644 FAX
FErtl@botanicals.com
Paul Bolar
Vice President, Regulatory & Legal Affairs
Pharmavite Corp.
P.O. Box 9606
Mission Hills, CA 91346-9606
(818) 837-3633
(818) 837-6109
pbolar@pharmavite.net
Michael McGuffin
McZand Herbal, Inc.
P.O. Box 5312
Santa Monica, CA 90409
(310) 822-0500
(310) 574-2721 FAX
mmherbal@flash.net
FDA Staff
Lynn A. Larsen, Ph.D.
Executive Secretary, Food Advisory Committee
(HFS-455)
Center for Food Safety and Applied Nutrition
Food and Drug Administration,
FB-8, Rm. 2831C
200 C Street, S.W.
Washington, D.C. 20204
(202) 205-4727
(202) 260- 8957 FAX
Llarsen@Bangate.FDA.Gov
Karen Strauss, M.S., R.D.
Division of Programs & Enforcement Policy
(HFS-456)
Office of Special Nutritionals
Center for Food Safety and Applied Nutrition
Food and Drug Administration,
FB-8, Rm. 2415C
200 C Street, S.W.
Washington, D.C. 20204
(202) 205-5123
(202) 260-8957 FAX
kfs@cfsan.fda.gov
kstrauss@bangate.fda.gov
Jill Ellis, Ph.D.
Director of Science and Quality Assurance
National Nutritional Foods Association
3931 MacArthur Boulevard, Suite 101
Newport Beach, CA 92660
(949) 622-6272, Ext. 229
(949) 622-6266 FAX
jellis@nnfa.org
William R. Obermeyer, Jr., Ph.D.
Division of Natural Products (HFS-347)
Office of Plant & Dairy Foods and Beverages
Center for Food Safety and Applied Nutrition
Food and Drug Administration,
FB-8, Rm. 5032
200 C Street, S.W.
Washington, D.C. 20204
(202) 205-4834
(202) 260-4422 FAX
wobermey@bangate.fda.gov
Christine J. Lewis, Ph.D., RD
Special Assistant, Office of Special
Nutritionals (HFS-451)
Center for Food Safety and Applied
Nutrition
Food and Drug Administration,
FB-8, Rm. 2804
200 C Street, S.W.
Washington, D.C. 20204
(202) 205-4434
(202) 205-5295 FAX
CLewis1@Bangate.FDA.Gov, or
CJL@CFSAN.FDA.Gov
The outline portion of the Report first presents a glossary of terminology. Following this, the two charges to the Working Group regarding GMPs are addressed, i.e., adequate testing for identity of ingredients and records and records retention.
The general principles to be considered in determining the appropriate ingredient tests are outlined. Included are characteristics of the dietary supplement ingredient, of the test techniques available, of the testing environment, and of the ingredient test method validation. Characteristics of the ingredient type follow the dietary supplement categories specified in DSHEA without further definition.
Testing techniques include macroscopic/organoleptic, microscopic, and chemical. The conditions affecting the conduct of the tests, i.e., the testing environment, are personnel, equipment, and laboratory supplies.
For records and retention, the outline generally follows the manufacturing process with sections for records pertaining to personnel, receiving ingredients, testing ingredients, production, distribution, and post distribution complaints. The need for written operational procedures and records to document their day-to-day use, as well as quality control materials and documents are addressed.
Topical detail is provided in several appendices. Appendices include reference citations for various aspects of testing, e.g., for available test methodologies, determining test method validity, and selecting a representative sample from a batch/lot. The appendices also include desirable elements in a CofA a checklist useful in evaluating a supplier's CofA, a survey for evaluating the ability of a supplier's operation to produce wholesome and pure products, and a case study.
Acceptance Criteria: Acceptance criteria means the product specifications such as specified limits for the amount of the ingredient, amount or presence of contaminants, impurities, and foreign material, and etc., that are necessary for making a decision to accept or reject a lot or batch (or any other convenient subgroups of manufactured units).
Adulteration: A food shall be considered to be adulterated if it bears or contains any poisonous or deleterious substance which makes it injurious to health as defined by the Food, Drug, and Cosmetic Act, section 402, and as appropriate in accordance with 21 CFR §110 Food, § 113 Thermally Processed Low-Acid Foods Packaged in Hermetically Sealed Containers, § 123 Fish and Fishery Products, and § 131 Milk and Cream.
AOAC: AOAC International, formerly the Association of Official Analytical Chemists, methods are recognized worldwide as authoritative because of their thorough and rigorous testing and characterization. Where the method of analysis is not prescribed in a regulation, it is the policy of the US Food and Drug Administration in its enforcement programs to utilize the methods of analysis of the AOAC as published in the latest edition (13 Ed., 1980) of their publication "Official Methods of Analysis of the Association of Official Analytical Chemists," and the supplements thereto.
Batch: Batch or lot means a specific quantity of a dietary ingredient, dietary supplement, or other material that is intended to have uniform composition, character, and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture.
Botanical: Botanical means plant or plant parts including bark, woods, leaves, stems, roots, flowers, fruits, seeds, berries, or parts thereof, as well as exudates. Botanical raw material means fresh or processed (i.e., cleaned, frozen, dried, sliced, etc.) plant materials, macroscopic fungi, or algae for the manufacture of dietary supplements. Different parts of the same plant, fungus, or alga are considered distinct botanical raw materials if they can be used separately for their respective values.
A botanical product means a finished, labeled product that contains as ingredients vegetal matters or their constituents, which include, but are not limited to: plant materials, algae, macroscopic fungi, etc., or combinations thereof.
Certificate of Analysis: A certificate of analysis is a statement from the supplier about the identity, strength, quality, and purity of a dietary supplement raw material or ingredient or finished product.
Cultivated: Cultivated means botanical plants that are produced (grown or tended) as a crop.
Dietary Ingredient: Dietary ingredient means any raw or processed ingredient intended for use in the manufacture of a dietary supplement, including those that may not appear in such finished product including dietary ingredients as defined in 21 USC 321 (ff) and 21 USC 321(5).
In-Process Material: In-process material means any material fabricated, compounded, blended, ground, extracted, sifted, sterilized, derived by chemical reaction or processed in any other way that is produced for, and used in, the preparation of a dietary product.
Manufacture: Manufacture or manufacturing includes all operations associated with the production of dietary products, including the firm or person who receives botanical raw materials in whole form, whether fresh (i.e., not dehydrated) or dried, for any processing other than dehydration (including but not limited to cleaning, grinding, tableting, encapsulating, extracting, etc.), whether for further distribution or for direct use in manufacturing; packaging and labeling operations; testing; and quality control of a dietary ingredient or dietary supplement.
Microorganism: Microorganisms or microbial when used as an adjective means yeasts, molds, bacteria, and viruses and includes, but is not limited to, species having public health significance.
Processor: Processor means a manufacturer (a firm or person) who receives botanical raw materials in whole form, whether fresh (i.e., not dehydrated) or dried, for any processing other than dehydration (including but not limited to cleaning, grinding, tableting, encapsulating, extracting, etc.), whether for further distribution or for direct use in manufacturing.
Representative Sample: Representative sample means a sample that consists of a number of units that are drawn based on rational criteria, such as random sampling, and is intended to assure that the sample accurately portrays the material being sampled.
Specification: A specification is a list of tests, references to analytical procedures, and appropriate acceptance criteria with numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a substance or dietary supplement product, or materials at other stages of their manufacture should conform to be considered acceptable for their intended use. Specifications are one part of a total control strategy designed to ensure product quality and consistency. Specifications for assuring the identity of an ingredient should be sufficiently precise to distinguish the ingredient from other ingredients that could be confused with the desired ingredient including potential and known adulterants.
Standard Reference Material: A reference material is a highly purified compound that is well characterized. Two categories of reference materials are 1) compendial reference standard (e.g., USP/NF) that does not need characterization and 2) non-compendial standard that should be of the highest purity that can be obtained by reasonable effort and should be thoroughly characterized to assure its identify, strength, quality and purity.
If a compendial reference standard is not available, the manufacturer should have established appropriately characterized in-house primary reference materials, prepared from lot(s) representative of production and clinical materials. In-house working reference material(s) used in the testing of production lots should be calibrated against this primary reference material. Where an international or national standard is available and appropriate, reference materials should be calibrated against it. While it is desirable to use the same reference materials for both biological assays and physiochemical testing, in some cases, it is possible that a separate reference material may be necessary. Also, it is possible that distinct reference materials for product-related substances, product-related impurities, and process-related impurities may need to be established.
In-house primary reference materials: A primary reference material is an appropriately characterized material prepared by the manufacturer from a representative lot(s) for the purpose of biological assay and physiochemical testing of subsequent lots and against which in-house working reference material is calibrated. The in-house reference material should be sufficiently well characterized to assure the accurate identity of the reference material.
In-house working reference material is a material prepared similarly to the primary reference material and is established solely to assess and control subsequent lots for the individual attribute in question. It is always calibrated against the in-house primary reference material.
An authenticated plant reference material is material that has been authenticated as the correct plant species and correct plant part(s) by a qualified plant taxonomist. It is permissible to use authenticated plant reference material to accurately identify in-house working reference material, which then becomes a working reference.
Training, Education: Training, education means attainment of knowledge, skills, and abilities pertinent to the position held. It is permissible to gain knowledge, skills, and abilities through relevant academic studies, trade association seminars and workshops, and on-the-job activities in addition to continuing education through relevant courses, seminars, or workshops.
Validation: Validation means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled.
Wildcrafted: Wildcrafted means a plant occurring or growing in a natural state; not cultivated or farmed.
Note: The focus here is identity testing. However, these principles are applicable also to testing for adulterants. (See also Appendix A: Considerations in Determining Adulteration of Dietary Supplements.)
Morphological characters and organoleptic characteristics are used in some cases to validate the identity of botanical ingredients at the time of collection or for unprocessed botanicals. When sufficient morphological characters are present to separate the plant species from other plant species, then an accurate identification can be made since morphological characters are the sole basis of distinguishing most of the world's plant species. However, unprocessed botanicals that do not contain all the plant parts necessary to include adequate morphological characters to assure the correct species should have other identity aids or tests to assure the identity of the botanical. For example, it is possible to use only a picture as an identity standard for whole fresh Ginkgo leaf from a cultivated field as it is not easily confused with the leaf shape, venation, and color of other leaves that could be present in the field. But powdered Ginkgo leaf is a different form of the ingredient and requires microscopic and/or chemical analysis. Ginkgo extracts have no morphological or anatomical features and it is possible that extracts may include a number of chemical compounds at different ratios and concentrations that would require a different chemical test to assure the identity of the ingredient.
The origin or source of a botanical is important since the kind of identity tests that will be necessary to assure the identity of the plant is dependent on the number of plants that could be confused with the desired plant. As an example, a cultivated field of St. John's Wort (Hypericum perforatum L.) that was grown from seed or plant stock that had been certified or the field inspected by a botanist competent in determining the species in the field would be all that is required to assure the identity of the unprocessed plant material. However, if the source of St. John's Wort (H. perforatum L.) was collected from the wild where other species of Hypericum could be confused with it, then collection guidelines and identity tests would need to be established to assure that only the correct species of St. John's Wort (H. perforatum L.) was present. (See Appendix B, Reference Citations for Testing Methods).
Herb or botanical ingredients include:
Testing techniques include:
(1) Defined morphological and/or anatomical characteristics of the whole plant or individual plant parts (e.g., leaf, flower, fruit, seed, root and rhizome, bark) and
(2) Characteristic color, fracture, smell, or taste.
(1) It is possible that processing variables may promote some difference in taste or colors of herbal raw materials, thus confounding proper and positive identification by macroscopic or organoleptic techniques. In order to overcome this concern, controls or limits for such variables need to be included in the manufacturer's protocols.
(2) It is possible that reliance on taxonomic or botanical characters including macroscopic, anatomical, and organoleptic characteristics alone may not confirm identity and may not detect adulterants unless the tests are sufficiently precise to distinguish the species from those that it can be confused with in the area that the botanical was collected.
(3) The harvest of plants for use as dietary ingredients often does not coincide with the plant's flowering season. All of the distinguishing morphological characteristics of the plant are not present at such times. While this is not always a significant obstacle to identification, a manufacturer should use good judgment in determining whether this technique can effectively identify plant material at such times without an identity test that has been proven to distinguish the desired species from know and potential adulterants where the botanical is collected.
(4) In the case of plants harvested from wild populations, it is possible that material from different locations and different collectors may be mixed prior to identification by the representative specimen. The integrity of such methodology is suspect in such situations unless the training of collectors and shipping of the material is sufficient to assure the proper identity of all the material and that sampling protocols are designed to detect the adulteration of heterogeneous lots of material.
(1) Defined histological characteristics of plant parts (e.g. stems, roots and rhizomes, bark, leaves, flowers, seeds, wood);
(2) Defined histological characteristics of animal tissues and cells; and
(3) Defined staining or microscopic chemical reactions.
(1) While microscopy can be used in the identification of ingredients, additional quality or purity data (e.g., contamination by mold, insect, rodent hair, microbe, heavy metal, and economic substitution) can also be obtained from microscopy and
(2) It is possible that finely powdered material may obliterate microscopic characteristics. In this case, other tests such as chemical assays should be employed.
(1) Chromatography is used for quantitative and qualitative analysis of:
(a) Raw bulk material or finished product;
(b) Process impurities;
(c) Residual solvents;
(d) Preservatives;
(e) Degradation products; and
(f) Adulterants.
(2) Chromatographic analytical techniques include:
(a) High Performance Liquid Chromatography (HPLC);
(b) Gas Chromatography (GC); and
(c) Thin-Layer Chromatography (TLC).
(1) Spectrographic:
(a) Ultra violet (UV);
(b) Infra red (IR);
(c) Fourier transformed infra red (FTIR); and
(d) Mass separation.
(2) Gravimetric;
(3) Titration;
(4) Capillary electrophoresis (CE); and
(5) Polymerase chain reaction (PCR) amplification of DNA.
(1) Validated chemical methods are lacking for many dietary supplement ingredients;
(2) All chemical methods rely on the quality, stability and purity of the reference standard and the stability of the analyte in a sample; and
(3) Sources of reference standards are lacking for many dietary supplement ingredients.
(1) Use of the test on multiple occasions or in multiple test facilities to evaluate the test method and present data for validation (in preferential order):
(a) In an inter-laboratory collaborative study (using numerous laboratories);
(b) in a second or third laboratory; or
(c) within an on-site laboratory.
(2) Use of method validation performance parameters such as:
(a) Accuracy;
(b) Detection limit;
(c) Quantitation limit;
(d) Linearity;
(e) Precision (injection and analysis repeatability, intermediate precision, and reproducibility);
(f) Range;
(g) Recovery;
(h) Robustness;
(i) Sample solution stability;
(j) Specificity/selectivity; and
(k) System suitability specifications and tests:
(1) Capacity factor;
(2) Precision/injection repeatability;
(3) Relative retention;
(4) Resolution;
(5) Tailing factor; and
(6) Theoretical plate number.
(1) Name and address of the supplier and date CofA attested to;
(2) Name and address of the processor (if appropriate) and type of manufacturing process (e.g., pulverization, decoction, expression, aqueous extraction, ethanolic extraction, and etc.,);
(3) Name of ingredient;
(4) Name, qualifications, and title of person certifying the analysis;
(5) Lot number;
(6) Chemical class of the constituent(s) or characteristic marker(s), if known and if relevant to the identity of the ingredient;
(7) Description of test(s) conducted to confirm identity of the raw material or ingredient. (Note: Tests for adulteration should also be included.);
(8) Test specifications and results;
(9) Identification of standard reference material (identified by number to facilitate trace back) and reference data used to confirm identity; and
(10) Concluding statement that confirms identity based on test results.
(1) Common and/or usual names of the material and the Latin name of the species (see Herbs of Commerce, 1992 or subsequent edition if the material is not listed in Herbs of Commerce, The CofA must use the complete Latin name.);
(2) Range of dates and locations of harvest, stage of plant development, and plant parts collected;
(3) Whether wild-crafted or cultivated; and
(4) Morphological description for the whole plant and anatomical characteristics of the plant part(s) of commerce.
(1) Material specification;
(2) Physical properties;
(3) Assay method; and
(4) Assay test results.
(1) Item (e.g., specified as species, tissue, extract, and concentrate);
(2) Origin (e.g., country, region);
(3) Description;
(4) Product specifications;
(5) Composition;
(6) Product treatment; and
(7) Assay test results (e.g., protein, mucopolysaccharides, enzymes, and extracts).
(1) Assessment of completeness of supplier's CofA (see also Appendix E, Desirable Elements of a Certification of Analysis) and
(2) Assessment of reliability of supplier's CofA (see also Appendix F, Reliability Audit of Suppliers Certificate of Analysis).
(1) One year after expiration of the lot's shelf life, or
(2) Three years from the date of manufacture.
VI. Appendices:
A. Considerations in Determining Adulteration of Dietary Supplements
B. Reference Citations for Testing Methods.
C. Reference Citations for Validating Test Methods.
D. Reference Citations for Sampling Methods.
E. Desirable Elements of a Certification of Analysis
F. Reliability Audit of Suppliers Certificate of Analysis.
G. Case Study (Plantain and digitalis).
H. Supplier Quality Survey of Desirable Characteristics for Issues Related to the Purity and Wholesomeness of Products.
APPENDIX A:
Considerations in Determining Adulteration of Dietary Supplements:
Adulteration is defined fined in the Food, Drug, and Cosmetic Act, Section 402.
Ingredients may be adulterated by and not limited to
a. Accidental inclusion of substance,
b. Substitution of less expensive but similarly testing ingredients,
c. Deliberate addition of non-declared substances,
d. Filth, pesticides
e. Naturally occurring toxicants
f. Microorganisms
Examples of natural hazardous adulterants associated with an ingredient include but are not limited to (see also 21 CFR Part 189, Substance Prohibited from Use in Human Food)
(1) Alkanna tinctoria,
(2) Anchusa officinalis,
(3) Borago officinalis,
(4) Crotalaria spp.,
(5) Cynoglossum spp.,
(6) Erechtites hieraciifolia,
(7) Eupatorium cannabinum,
(8) Eupatorium purpureum,
(9) Heliotropium spp.,
(10) Lithospermum officinale,
(11) Packera candidissima,
(12) Petasites spp.,
(13) Pulmonaria spp.,
(14) Senecio jacobaea,
(15) Senecio vulgaris
(16) Symphytum asperum,
(17) Symphytum spp.,
(18) Symphytum x uplandicum,
(19) Symphytum officinale, and
(20) Tussilago farfara.
APPENDIX B
Reference Citations for Testing Methods
A Practical Guide to HPLC Detection, Parriott, D. editor, Academic Press, Inc., 1993.
American Herbal Pharmacopeia and Therapeutic Compendium, Upton, R. Editor, American Herbal Pharmacopoeia, Santa Cruz, CA.
American Herbal Products Association's Botanical Safety Handbook, eds., M. McGuffin, C. Hobbs, R. Upton, and A. Goldberg, CRC Press, Boca Raton1997.
Ausubel, F.M., R. Brent, R.E. Kingston, D.D. Moore, J. G. Seidman, J. A. Smith, and K. Struhl, Current Protocols in Molecular Biology. John Wiley and Sons, New York, 1995. (Note: This book is updated quarterly).
Bensky, D. and A. Gamble, Chinese Herbal Medicine Materia Medica, Eastland Press, Inc. P.O. Box 12689, Seattle, WA 98111, 1993.
Blumenthal M. and C. Riggins, Popular Herbs in the U.S. Market, Therapeutic Monographs, The University of Texas, College of Pharmacy, 1997.
Blumenthal, M., W. R. Busse, A. Goldberg, J. Gruenwald, T. Hall, C. W. Riggins, and R. S. Rister, The Complete German Commission E Monographs Therapeutic Guide to Herbal Medicines, The American Botanical Council, Austin, Texas, 1998.
British Herbal Pharmacopeia, British Herbal Medicine Association, P.O. Box 304, Bournemouth, Dorset BH7 6J2, 1996.
British Pharmacopoeia, British Pharmacopoeia Commission, Market Towers, 1 nine Elms Lane, London SW8 5NQ, 1993.
British Herbal Compendium, Bradley P., editor, British Herbal Medicine Association, P.O. Box 304, Bournemouth, Dorset BH7 6J2, 1992.
British Standards Institute (catalog of methods), 389 Chiswick high Road, London W4 4AL United Kingdom.
Compendium of Methods for the Microbiological Examination of Foods, 3rd ed., Vandergant C. and Splittstoesser, D.F. editors, American Public Health Association, 1015 15th St. N.W., Washington, D.C., 20005, 1992.
Downstream Processing of Natural Products: A Practical Handbook, Verrall, M. editor. John Wiley and Sons, Inc., 1996.
European Pharmacopoeia, European Department for the Quality of Medicines, Council of Europe Publishing, 67075 Strasbourg Cedex France, 1999.
European Scientific Cooperative on Phytotherapy (ESCOP) Monographs on the Medicinal Uses of Plant Drugs, Argyle House, Gandy Street, Exeter, Devon EX4 3LS UK, 1997.
FDA Bacteriological Analytical Manual, 8th ed., AOAC International, 481 N. Frederick Ave. Suite 500, Gaithersburg, MD 20877, 1995.
FDA Laboratory Procedures Manual, Department of Health and Human Services, Public Health Service, Food and Drug Administration, Form 3350A (and subsequent updates), 1989.
Fitoterapia Monographs, Indena U.S.A. East, Inc., The Atrium, 80 East Route 4, Paramus, NJ 07652, 1998.
Foster and Duke, Peterson Field Guide Eastern/Central Medicinal Plants, Houghton Mifflin Co., 1998.
Gleason, H. A., The New Britton and Brown Illustrated Flora of the North Eastern United States and Adjacent Canada, The New York Botanical Garden, Lancaster Press, Inc., 1952.
Herbs of Commerce, American Herbal Products Association, Austin, Texas, 1992.
Jackson, B. P. and D. W. Snowdon, Atlas of Microscopy of Medicinal Plants, Culinary Herbs and Spices, CRC Press, Inc., 1990.
Manual on Botanical Adulteration (expected, 1999), American Herbal Products Association.
Martindale The Extra Pharmacopoeia, 31st ed., J. Reynold editor, Rittenhous, 1996.
Official and Standardized Methods of Analysis, 3rd ed. Watson, C.A. editor, The royal Society of Chemistry, Thomas Graham House, Science Park, Cambridge CB4 4WF, 1994.
Official Methods of Analysis, 16th Edition, Vols. I and II. AOAC International, 481 North Frederick Avenue, Suite 500, Gaithersburg, MD 20877-2504, 1998. The basic method and techniques used include: "Section 43.1.16 AOAC International, 16th ed., 1995, Official Method 916.01, Adulterants in Spices, Microscopic Examination Method, Procedure" with the modifications and additions.
Raffauf, R.F., Plant Alkaloids: a guide to their discovery and distribution, Haworth Press, Inc., 10 Alice Street, Binghamton, N.Y. 13904-1580, 1996.
Pharmacopoeia of the People's Republic of China, English Edition, The Pharmacopoeia Commission of the PRC, Guangdong Science and Technology Press, Guangzhou, 1992.
The Pharmacopeia Convention of the American Institute of Homeopathy, Homeopathic Convention of the United States, 4974 Quebec Street, NW, Washington, DC 20016.
The International Pharmacopoeia, 3rd ed., Vol. 4: World Health Organization, Geneva, 1994.
United States Pharmacopeia and the National Formulary (USP-NF), The United States Pharmacopeial Convention, Inc., Rockville, MD, 1998.
Wagner, H. and R Bauer, et al. Chinese Herb Monographs and Analysis,
Wagner H. and S. Bladt, Plant Drug Analysis: a thin layer chromatography atlas, (2nd ed), Springer-Verlag, New York, Inc., 1996.
Weston, A. and P. Brown, HPLC and CE: Principles and Practice, Academic Press, Inc., 1997.
Wichtl, M. And E. N. Grainger Bisset, Herbal Drugs and Phytopharmaceuticals, CRC Press, Inc., 1994.)
Williamson, E. M., F. J. Evans, and D. T. Okpako, Pharmacological Methods in Phytotherapy research, Vol. 1: Selection, Preparation, and Pharmacological Evaluation of Plant Material, John Wiley and Sons, Inc., 1996.
APPENDIX C
Reference Citations for Validating Test Methods
Reviewer Guidance, Validation of Chromatographic Methods, Center for Drug Evaluation and Research, FDA, November 1994.
International Conference on Harmonisation (ICH); Draft Guidance on Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products, Federal Register, 63:110, 31506-31513, June 9, 1998.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Text on Validation of Analytical Procedures, Recommended for Adoption at Step 4 of the ICH Process by the ICH Steering Committee, 1994.
Uniform Testing Methods for Botanicals Needed but Present Unique Challenges. Inside Laboratory Management AOAC International, May 1998.
Manual on Policies and Procedures, AOAC Peer-Verified Methods Program, AOAC International, 2200 Wilson Blvd, Suite 400, Arlington, VA 22201.
APPENDIX D:
Reference Citations for Sampling Methods
FDA Laboratory Procedures Manual, Department of Health and Human Services, Public Health Service, Food and Drug Administration, Form 3350A (and subsequent updates), 1989.
Horwitz, J. Focus on sampling: sampling and preparation of sample for chemical examination. J. Assoc. Off. Anal. Chem. 17:2, 241-245, 1988.
Nollet, L.M.L. Editor. Handbook of Food Analysis (2 Volumes), Marcel Dekker, New York City, 1996.
APPENDIX E:
Desirable Elements of a Certification of Analysis
a. Name and address of supplier.
b. Name, qualifications, and title of person certifying the analysis.
c. Harvest location and time (for botanical and animal materials).
d. Collection, washing, drying, preservation procedures, and etc. (if botanical).
e. Handling, transportation, and storage.
f. Name of material and specifications (if applicable).
g. Complete Latin name and common name or as referenced in Herbs of Commerce (if botanical).
h. Standardized reference material for analytical assays and identity test(s) conducted and technical reference materials used including written, visual and/or authenticated plant reference material for verification of material's identity (if botanical).
i. Retained representative sample material identified by number to facilitate trace back.
j. Appearance.
k. Physical and chemical properties (morphological and anatomical description for whole plant and plant part, if botanical).
l. Active constituent (if known).
m. Activity or strength by weight.
n. Validated test method(s) used.
o. Assay for active constituent or characteristics.
p. Assay for biological activity or biological assay, if available.
q. Assay for water (loss of drying).
r. Assay for analysis of foreign substances (e.g. unreacted materials, by products, adsorbed carbon dioxide).
s. Assay for optical light rotation of the isomers, if appropriate.
t. Chemical marker & measure (if applicable).
u. Name of manufacturer.
v. Manufacture process (e.g., pulverization, decoction, expression, aqueous extraction, and etc.).
w. Disclosure of solvents (if extract).
x. Heavy metals.
y. Microbial contamination and/or preformed endotoxins.
z. Radioactive materials.
aa. Pesticides/herbicides (if applicable).
bb. Foreign materials (e.g. filth, fungi).
cc. Concluding statements that confirm identity, purity, and activity (when appropriate) based on test results.
APPENDIX F
Reliability Audit of Suppliers Certificate of Analysis
For Botanical Collections
For Ingredient Processing
Testing
Records
APPENDIX G:
CASE STUDY (Plantain and digitalis)
APPENDIX H
Supplier Quality:
Survey of Desirable Characteristics for Production Issues Related to the Purity and Wholesomeness of Products
Manufacturer Information:
Company name.
Parent company (if different).
Plant address.
Mailing address (if different).
Telephone number, fax number, e-mail address.
Plant manager.
Quality assurance manager (if no quality assurance manager, indicate who is responsible for quality assurance activities.
Type of operation.
Is this facility inspected by a third party? If yes, name the organization and date of the most recent inspection and include a copy of the completed inspection report with this survey.
Ingredient Survey:
Material Control
Product Safety
Are there sifters in the system?
Type and size of sifter screen
Frequency of integrity checks.
Are frequency checks documented?
B. Liquid System
Are there strainers and/or filters in the system?
Location of all strainers and/or filters.
Type and mesh size of strainers and/or filters
Frequency of integrity checks.
Are frequency checks documented?
Type of magnets (ceramic, rare earth, etc.)
Frequency of integrity checks.
Are frequency checks documented?
Is there metal detection on finished product?
Brand of metal detectors?
Size and composition of test piece?
Are tests documented?
Frequency of sensitivity checks.
Are sensitivity checks documented?
Describe kick off/reject procedure.
Sanitation
Pest Management
If an exterminator service, please name the service company.
Other Good Manufacturing Practices
Is there a documented policy of no unprotected glass in the facility?
Is there a documented plant personnel GMP policy?
Briefly describe the plant requirements regarding hairnets, jewelry, uniforms, etc.
Other
Name, signature, and date of signature of person completing this form.
Name, signature, and date of signature of the officer of the company surveyed.
Surveyed company is approved or not approved as supplier.
Name, signature and date of signature for person evaluating survey.
FDA Fish and Fishery Products HACCP Regulations
The Working Group Members request agency confirmation that the FDA Fish and Fishery Products HACCP Regulations apply to dietary supplements when the characterizing ingredient is derived from fish and fishery products (e.g., fish oils and fish cartilage). The Report sections specific to written procedures and records for receiving materials (see Preface, page 1 and Outline V B 7, page 24, and Appendix H, Item 18) guides manufactures to seek records that demonstrate compliance with FDA Fish and Fishery Products HACCP Regulations. However, members are uncertain as to the applicability and extent of applicability of these HACCP Regulations to dietary supplements derived from fish or fishery products, in particular, since this information is not generally available to a manufacturer.
Reporting Serious Adverse Events to FDA
Some Members believe that the written procedures and records for handling complaints should guide manufactures to report serious adverse events to the FDA MEDWATCH system to ensure that the agency has information needed to protect public health (see Report Section V, Records and record retention, F, Written records and procedures for handling complains; page 26). Because of existing concerns about the current usefulness of the system this guidance is not included in the Report.
Performing Multiple Tests in Identifying Whole Plants and Whole Plant Parts
Some members are concerned that the principles outlined for performing multiple tests in identifying whole plants or whole plant parts (see Outline IV A, 3, a and b; page 13) and the exception noted (see Outline IV A, 3, e; page 14) might create a "loophole" that gives a means of escaping testing. Creating a loophole is not the intention. Rather, the intent is to emphasize the need for multiple testing and that sufficient identity tests should be performed to ensure that what is on the product label is true and accurate.
Use of Terms: "Validate, Validated, and Validation"
An unresolved issue remains in this document. Some members are concerned that the use of the terms "validate, validated, and validation" is too broad as it applies to the soundness and consistency of ingredient identity tests for a specific intended use. The terms "validated and validation" have specific meanings in the chemistry world that may not apply to all test methods. For example, the Report refers to "validated" methods for microscopy (when few microscopic methods involve validation) or for using "validated" methods for identifying extracts (although few exist). The Working Group hopes to bring resolution of this issue to the Food Advisory Committee at their June 25 meeting. The Working Group members expect to revise use of this term to more accurately identify the testing techniques where alternate terms such as "verify or verification" or "substantiate or substantiation" would be more appropriate.
Reliance on Authenticated Plant Reference Material
There is a concern that the recommended use throughout Sections IV and V and in Appendix E of "authenticated plant reference material" as defined in the Glossary is unnecessarily narrow. This position expresses a belief that the term "authenticated or other accurately identified plant reference material" provides more practical guidance. An alternate approach is to delete the words "by a qualified plant taxonomist" from the definition of an "authenticated plant reference material" or to change these words to "by a person qualified to make such determination." This position believes that such deletion is consistent with the inclusion of experiences other than academic studies in the Glossary definition of "Training, Education," and does not in any way lessen the recommendation that only plant material that has been positively identified be used as a reference.
Inclusion of Plaintain/Digitalis Case Study
A concern exists that the inclusion of a negative case study will be viewed by industry as unnecessarily critical and lead to an undue and inaccurate perception that the problem of mis-identification of dietary ingredients is widespread. This concern would be addressed by recommending that the agency consider excluding the case study from the proposed Guidance Document, as inclusion might create an obstacle to industry acceptance of the purpose of the Guidance Document as stated in Good Guidance Practices, FR (62) 39:8967.
This document was issued in June 1999.
For more recent information on Dietary Supplements
See
http://www.cfsan.fda.gov/~dms/supplmnt.html
Hypertext updated by ear/dms/kwg 2000-NOV-22