USP Botanical Quality Standards: Contributions In Quality Control .
USP botanical quality standards:contributions in quality control & safe use of botanicalsHellen Oketch-Rabah, PhDSenior Scientific Liaison, Dietary Supplements, Herbal MedicinesUNITED STATES PHARMACOPEIA2017 NCAC-SOT Spring SymposiumApril 19, 2017 Lister Hill Auditorium NIH Campus, Bethesda, MD
DISCLAIMER:Because USP text and publications may have legal implications in the U.S. and elsewhere,their language must stand on its own. The USP shall not provide an official ex post factointerpretation to one party, thereby placing other parties without that interpretation at a possibledisadvantage. The requirements shall be uniformly and equally available to all parties.In addition, USP shall not provide an official opinion as to whether a particular article does ordoes not comply with compendial requirements, except as part of an established USPverification or other conformity assessment program that is conducted separately from andindependent of USP's standard-setting activities.Certain commercial equipment, instruments or materials may be identified in this presentationto specify adequately the experimental procedure or illustrate a point. Such identification doesnot imply approval, endorsement, or certification by USP of a particular brand or product, nordoes it imply that the equipment, instrument or material is necessarily the best available for thepurpose or that any other brand or product was judged to be unsatisfactory or inadequate.Any views expressed in this presentation are solely the authors’ views3
AcknowledgementsI wish to thank the following for their contributions:USP:Dr. Gabriel I. GiancasproDr. Nandu D. SarmaMr. Doug PodolskyStudentsMs Mary Pothen, MS (Pharm. D candicate, University of Maryland)Ms. Kimberly Uwe, MS (Pharm. D candicate, University of Maryland)4
Outline of talk What is a USP DS qualitystandard: monographs, general noticesand general chapters, Ref. materials Development of USP DS quality monograph preceded by USPAdmission Evaluation that is based on safety evaluation How USP monographcontributes to public safety Message: USP DS quality standards for public safety5
Standard definedWhat is a standard?A standard is a document that provides requirements, specifications, guidelines orcharacteristics that can be used consistently to ensure that materials, products,processes and services are fit for their purpose.The International Organization for SP Public standards include Monographs that provide specifications:Specifications– Tests– Analytical Procedures– Acceptance Criteria6
USP Botanical DS Quality StandardsUSP Standards include:MonographsRelated USP General Chapters & General NoticesReference materialsTo comply with USP quality standard an article mustconform to all requirements : tests in a monograph(incl. referenced chapters) and General Notices
Dietary Supplements Monograph DevelopmentUSP NomenclatureAdmission EvaluationExpert PanelRecommendation8
USP Dietary Supplement Safety Review
USP Dietary Supplements Admission EvaluationInformation (evidence based):1. Ingredient characterization: characteristics of the material underreview (botanical power, extract etc.)2. Exposure: intake levels, route of administration (relevant is bymouth).3. Human data: safety studies, clinical studies, post-marketingsurveillance, adverse events (case reports, AER portals),interactions etc.4. Pharmacological data: reproductive toxicity, experimental animalstudies, pharmacokinetics, safety index, and presence of toxicconstituents5. Contemporaneous extent of use: globally and in the U.S.;including misuse and abuse6. Historical use: Globally7. Regulatory status: in the U.S. and other countries: regulatoryactions, OTC status, GRAS status, etc.8. Presence in other pharmacopeia
USP Quality Attributes in Specifications in a USP Monograph USP Compendial Standards: Monographs ContainsSpecifications Identity (Identification)Assay for content (Purity)Composition (Constituents)Absence of Contaminants (Contaminants)Impurities (impurities)Specific TestsOther requirements (labeling and packaging) Consistent with GMPs for DS
Specifications in a USP Dietary Ingredient MonographUSP Term(s)IdentificationAssay orContent of CompositionUSP Monograph Test CharacteristicsThe monograph section titled “Identification” may consist of one or more (orthogonal)tests to verify the identity of articles. Failure of the article to meet one or more of thetests under the identification section indicates that the article is mislabeled and/oradulterated.The USP monograph tests for Assay and Content of (specific constituent or marker)are used to measure the amount of a substance in an ingredient, which in FDA’slanguage is the overall purity of the ingredient. Conversely, the USP monograph testsfor impurities provide means to determine the portion of an ingredient that is not theintended component.Composition applies to multiple constituents in an ingredient.Contaminants may arise from any source extraneous to the manufacturing processand that is introduced by contamination or adulteration. Contaminants can beContaminants classified as microbiological (e.g., objectionable microorganisms) or chemical (e.g.,pesticides). Analytical procedures for the determination of contaminants can bequantitative assays or limit tests.Impurities may arise from the manufacture (e.g., reagents, byproducts) or storage(e.g., degradation) of an article. Impurities can be classified as organic or inorganic.ImpuritiesSetting impurity or degradation product limits for articles is based on chemistry andsafety concerns. Analytical procedures for the determination of impurities can bequantitative assays or limit tests.Specific tests are sometimes included to further characterize an article, such as testsfor the chemo-physical nature of fats and fixed oils (e.g., specific gravity, meltingSpecific Teststemperature), and the rancidity of fats and fixed oils (e.g., Peroxide Value, AnisidineValue).12
Quality attributes in USP monographs for dietarysupplementsUSP Term(s)IdentificationStrength, AssayContaminantsImpuritiesSpecific TestsPerformanceUSP Monograph Test CharacteristicsSee Identification in in the previous slideAssay test procedures are used to measure the strength of adietary ingredient in a dietary supplement. Assay testprocedures measure the concentration or amount of a dietaryingredient per unit serving of a dietary supplement. Strengthapplies only to finished dosage forms (dietary supplements).See Contaminants in in the previous slideSee Impurities in in the previous slideSee Specific Tests in the previous slidePerformance tests (e.g., disintegration, dissolution) are qualitycontrol tests to assess the release characteristics of finishedproducts.13
Example of a USP Botanical Monographe.g. FENUGREEKUSP Term(s)Test Characteristics in Probiotic MonographsIdentification (e.g. Genus species and Family), TLC/HPTLC, HPLC,Identificationmacroscopy and microscopyAssay orChromatography-HPLC, GC, etc.Content of Composition Chromatography-HPLC, GC, etc.Contaminants Microbial contaminants (e.g. E coli, Salmonella species)ImpuritiesHeavy metals, herbicides and pesticidesSpecific Tests Macroscopy and microscopy, loss on drying, ash, etc.14
USP General Chapters Specific for Dietary Supplements 2021 Microbial Enumeration Tests, Nutritional and Dietary Supplements 2022 Microbiological Procedures for Absence of Specified Microorganisms,Nutritional and Dietary Supplements 2023 Microbiological Attributes of Non-sterile Nutritional and Dietary Supplements 2040 Disintegration and Dissolution of Dietary Supplements 2091 Weight Variation of Dietary Supplements 2232 Elemental Impurities in Dietary Supplements 2750 Manufacturing Practices for Dietary Supplements
USP General Chapters Non Specific for Dietary Supplements 203 233 211 251 411 467 561 563 621 731 HPTLC for Botanical IdentificationElemental Impurities - ProceduresArsenicLeadFolic acidResidual SolventsArticles of Botanical OriginIdentification of Articles of Botanical OriginChromatographyLoss on Drying
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Specifications in a USP Dietary Ingredient MonographUSP Term(s)USP Monograph Test CharacteristicsThe monograph section titled “Identification” may consist of one or more(orthogonal) tests to verify the identity of articles. Failure of the article to meetIdentificationone or more of the tests under the identification section indicates that thearticle is mislabeled and/or adulterated.The USP monograph tests for Assay and Content of (specific constituent orAssay ormarker) are used to measure the amount of a substance in an ingredient,Content of (which in FDA’s language is the overall purity of the ingredient).Composition Composition applies to multiple constituents in an ingredient.Contaminants may arise from any source extraneous to the manufacturingprocess or may be introduced by contamination or adulteration. ContaminantsContaminants can be classified as microbiological (e.g., objectionable microorganisms) orchemical (e.g., pesticides). Analytical procedures for the determination ofcontaminants can be quantitative assays or limit tests.ImpuritiesImpurities may arise from the manufacture (e.g., reagents, byproducts) orstorage (e.g., degradation) of an article. Impurities can be classified as organicor inorganic. Setting impurity or degradation product limits for articles is basedon chemistry and safety concerns. Analytical procedures for the determinationof impurities can be quantitative assays or limit tests.Specific tests are sometimes included to further characterize an article, suchSpecific Tests as tests for the chemo-physical nature of botanicals: macroscopy andmicroscopy fall here24
Specifications in a USP Dietary Ingredient MonographUSP Term(s)USP Monograph Test CharacteristicsThe monograph section titled “Identification” may consist ofone or more (orthogonal) tests to verify the identity of articles.Identification Failure of the article to meet one or more of the tests under theidentification section indicates that the article is mislabeledand/or adulterated.Plantain mixed with/substituted with Digitalis in 1998: Remember the case of plantain mixed with Digitalis lanata in 1998 The C of A for the raw plant material had a description of certain of its physicalcharacteristics, such as “color and flavor” only no chemical testing. If orthogonal test had been used to identify the raw material chances of passing wouldhave been reduced significantly.25
Content/Strength and CompositionCompositionComposition applies to multiple constituents in an ingredient. It may look right but strength may not be: may be weaker than required thusno beneficial effects-Black cohosh products But adulterated/ratio of different components– Weight loss products– Performance enhancement products– Sexual enhancement products26
Ginkgo biloba123456Test for flavonoids - HPTLCTrack assignment: 1) USP Rutin RS 0.6 mg/mL, USP Chlorogenic RS0.2 mg/mL, and USP Quercetin RS (with increasing RF); 2) ginkgoleaves (commercial sample); 3) ginkgo leaves (wild crafted); 4) ginkgoleaves, powder (commercial sample A); 5) ginkgo leaves, powder(commercial sample B); 6) ginkgo leaves, tincture (commercial sample)Content of flavonol glycosides – HPLC123456123456Test for terpene lactones – HPTLCTrack assignment: 1) bilobalide (commercial sample), 1 mg/mL; 2) USP Ginkgo Terpene Lactones RS, 10 mg/mL; 3) ginkgoleaves (commercial sample); 4) ginkgo leaves (wild crafted); 5) ginkgo leaves, powder (commercial sample A); 6) ginkgoleaves, powder (commercial sample B)Left image: Derivatize, heat at 180º for 10 min, cool, and examine under UV light at 254 nm;Right image: Derivatize, heat at 180º for 10 min, cool, and at 366 nmGinkgo Terpene Lactones - HPLCGinkgolic Acids - HPLC27
Performance-Dosage forms If the material does not disintegrate you may end up with adverse effectintestinal obstruction, chocking Will not get the effect required Examples:– prebiotics such as psyllium, inulin– vitamins28
ContaminantsContaminantsContaminants may arise from any source extraneousto the manufacturing process or may be introducedby contamination or adulteration. Contaminants canbe classified as microbiological (e.g., objectionablemicroorganisms) or chemical (e.g., pesticides).Analytical procedures for the determination ofcontaminants can be quantitative assays or limittests. Microbial contamination –may leads to infection and other adverse effects Heavy metals poisoning – examples of some dietary supplementscontaining heavy metals e.g. botanical DS adopted from Ayurveda medicalsystem have been found in the USA market29
ImpuritiesImpurities may arise from the manufacture (e.g., reagents,byproducts) or storage (e.g., degradation) of an article.Impurities can be classified as organic or inorganic. SettingImpurities impurity or degradation product limits for articles is basedon chemistry and safety concerns. Analytical proceduresfor the determination of impurities can be quantitativeassays or limit tests. Creatine– Depending on manufacture method may be contaminated with cancercausing agents such as dihydrotriazineComfrey– Depending on manufacture method may be contaminated with hepatotoxicpyrrolizidine alkaloidsTryptophan– Depending on manufacture method May be contaminated with EBT thatcan cause eosinophilia myalgia syndrome (EMS)30
Labeling Section of the MonographInstructions on what goes on the labelTo comply with cGMPs Ensure safetyThe label of an herb or other botanical intended for use as a dietarysupplement (that claim to comply to USP standards) shall bear the statement,“If you are pregnant or nursing a baby, seek the advice of a health professionalbefore using this product.” unless exempt. Admission may be pegged to the inclusion of warning statement e.g. forBlack cohosh, St Jon’s Wort, Willow Bark31
Example of labels to protect public St. Johns Wort: The label bears a statement indicating that “Rare cases ofallergic reactions and photosensitivity have been reported with the use of St.John’s Wort. St. John’s Wort interacts with numerous medications. Checkwith your healthcare provider before using.” Black Cohosh: Dosage forms prepared with this article should bear thefollowing statement: Discontinue use and consult a healthcare practitioner ifyou have a liver disorder or develop symptoms of liver trouble, such asabdominal pain, dark urine, or jaundice. Willow Bark: The label bears a statement indicating “Not for use in children,women who are pregnant or nursing, or by persons with known sensitivity toaspirin”.32
In conclusion USP DS quality standards are developed with input form EC (from differentdisciplines) thus have the best possible information Public/stakeholder input sought (PF) and incorporated Ensure public receives quality OTC and DS products Monograph attributes each designed to protect public health as discussed Products that comply with USP quality standards protect public health and inpublic interest33
for the chemo-physical nature of fats and fixed oils (e.g., specific gravity, melting temperature), and the rancidity of fats and fixed oils (e.g., Peroxide Value, Anisidine Value). Specifications in a USP Dietary Ingredient Monograph
USP Reference Standards for USP or NF. section, under Quantitative determinations, the text is revised as follows: ”For the USP Reference Standards where an International Standard (IS) established by the WHO exists, the reference standards documentation will indicate when the USP RS has been established by
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Y-site compatible with several IV bag fluids, including: — Water for Injection, USP — 0.9% Sodium Chloride Injection, USP — Lactated Ringer’s Injection, USP — 10% Amino Acid — 5% Dextrose Injection, USP — 5% Dextrose in 0.9% Sodium Chloride Injection, USP — 5% Dextrose in Lactated Ringer’s Injection, USP Titrate DOSE .
Apr 08, 2021 · About United States Pharmacopeia (USP) USP, a scientific organization that sets standards for identity, strength, quality, and purity of medicines, food ingredients, and . Follow containment requirements in USP 800 Perform an Assessment o
DNA-based methods would complement the current USP chemical and botanical methods for the identification of these articles. USP general chapter best-practice guidelines, monograph methods and reference standards would bring . DNA testing is an evolving science and not presently recommended as a stand alone ID test method.
In December 2014, a new version of USP 791 officially went into effect. This version of 791 is part of the Second Supplement to USP 37-NF 32. pH measurements within the pharmaceutical industry often reference USP 791 . Thermo Scientific Orion pH meter kits are part of a high-quality pH test method designed to assist with compliance to USP
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DSC USP–NF General Chapters25 USP–NF General Chapters This section contains selected official general chapters that are reprinted from the USP.Only those USP chapters considered relevant for the analysis and/or manufacturing of dietary supplements are included in this section.
