USP Botanical standards – a comprehensive approach to quality

Complementary Medicines Australia, October 09, 2019

Nandu Sarma, Ph.D.,Director, Dietary Supplements and Herbal Medicines

2© 2017 USP

Outline USP’s public standard-setting process

and regulatory recognition

Botanical drugs and dietary supplements – quality requirements

Unique challenges and complexities of botanical ingredients

Emerging topics in botanical quality controls

2© 2018 USP

Who we are

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We exist to …▸ Protect patient safety▸ Advance public health▸ Foster competition for more affordable

quality medicines

We are an ‘organization of organizations’▸ Governed by the USP Convention▸ 450 academic institutions; healthcare

practitioner, patient and industry groups; and governmental orgs

We are science-based▸ Not-for-profit and independent

We are powered by …▸ 900+ experts from science and health who set USP

quality standards▸ 100 FDA staff participate in the process

About USP

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USP standards are set by Expert Committees

Expert Committees

Board of Trustees &

Board Committees USP Staff

AdvisoryBodies

Expert Panels

Workinggroups

Stakeholderforums

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The Experts Behind Our Standards

2015–2020 Expert Committees

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USP – Public Standards

Hello, user

USP standards used in over 140 countries

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Monographs

General Test Chapters

General Notices (GN)

USP–NF

USP Monographs, General Chapters and General Notices

General Notices provides the basic assumptions and definitions for applying USP−NF compendialstandards, which are applied to official articles recognized in monographs and any applicable general chapters

General Chapters contain requirements applicable to monographs to which they apply

Monograph requirements are specific to the monograph in which they appear. Monograph requirements supersede General Notice and General Chapter requirements in case of a conflict

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New Dietary Supplements Compendium Online

Online.uspdsc.com/

500+ dietary supplement monographs

170 General Chapters

> 175 excipient (NF) monographs

> 200 Food Chemicals Codex (FCC) monographs

68 DSC admission evaluations

>150 added pages of color plates and illustrations

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https://hmc.usp.org

Herbal Medicines Compendium (HMC)

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USP Reference Standards- A benchmark for quality

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Developing Standards

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Dietary Supplement Admission Evaluation Process

Evaluation of Information by EC

https://www.usp.org/sites/default/files/usp/document/get-involved/submission-guidelines/guideline-for-the-admission-of-dietary-supplement-ingredients.pdf

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USP publications

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Factors impacting pharmacopeial standards

Regulations – DSHEA and DSHEA-like –Compliance with Pharmacopeia: Voluntary or mandatory

Global supply chain

New technologies

Adulteration

Contaminants, such as pesticide residues

Partners in industry

R&D companies and generic

manufacturers

Partners in science With academics,

practitioners

Partners in governmentWith regulatory and health authorities

Partnerships at the heart of quality

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USP Standards in the Law

Federal Food, Drug, and Cosmetic ActSections 201 (g) and (j), 501(b), 502(g)USP and NF standards FDA enforceable for all drugs.Conformance is generally not optional.

Dietary Supplement Health & Education Act (DSHEA)Section 403(s)(2)(D) of the FD&C ActA dietary supplement represented as conforming to specifications from an official compendium (USP-NF) shall be deemed misbranded if it fails to do so. FDA enforceable.

Conformance is optional.

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Preamble to the 2003 CGMP Proposal (68 FR 12157 at 12208 and 12209):

Validated methods and the role of the official compendia: “We explicitly stated that you may use validated methods that can be found in official references, such as AOAC International, USP, and others.”

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Use of Compendial Standards

Use of compendial reference standards: “…we noted that compendial standards may be appropriate reference materials for use in conducting tests or examinations.”

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Failed to ensure that the tests are appropriate, scientifically valid methods, as required by 21 CFR 111.75(h)(1). Specifically:

•Black cohosh and ashwagandha: Organoleptic analysis of appearance, color, odor, and taste. No RS and no written acceptance criteria to define any of these characteristics.

•Kelp and ashwagandha: Identification using FTIR. The RS used to compare the spectra were a previous lot of kelp and ashwagandha. There was no written acceptance criteria established for the passing identification test.

Non-compendia reference standard materials should be of the highest purity by reasonable effort and should be thoroughly characterized to ensure their identity, purity, quality, and strength.

Common GMP violation: Failure to meet requirement for scientifically valid methods

http://www.fda.gov/iceci/enforcementactions/warningletters/2014/ucm417209.htm

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Recognition of USP standards in Australia

https://www.tga.gov.au/publication/compositional-guidelines

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Outline USP’s public standard-setting process

Botanical drugs and dietary supplements – quality requirements

Unique challenges and complexities of botanical ingredients

Emerging topics in botanical quality controls

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GMPs require specifications for quality

“Quality means that the dietary supplement consistently meets the established specifications for identity, purity, strength, and composition, and limits on contaminants,…”

− §111.75(a)(1)(i) Your must conduct at least one appropriate test or examination to verify the identity ...

− §111.75 (h)(1) You must ensure that the tests and …the specifications are .. appropriate, scientifically valid methods.

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Specifications

Specification:– a list of tests, – analytical procedures, and – appropriate acceptance criteria

The set of criteria to which a .. product should conform to be considered acceptable for its intended use.

Critical quality standards that are proposed and justified by the manufacturer.

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Intact plant material-------------------------------------------------------------------------------------------------------------------Single chemical entity

Whole

Turmeric Root

Powdered plant material

Native/Full spectrumExtracts

Enriched Extracts

IsolatedClass of compounds

PurifiedSingle Chemical

TurmericPowder

TurmericDry Extract

Turmeric CurcuminoidExtract

Curcuminoids Curcumin

Degree of Purification

Degree of Complexity

Complexity of Natural Products

http://www.usp.org/sites/default/files/usp/document/get-involved/submission-guidelines/guideline-for-assigning-titles-to-usp-dietary-supplement-monograph.pdf

Degree of Purification

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Botanicals in USP

Drugs Excipients• Acacia• Mint• Tragacanth• Cardamom• Vanilla• Cinnamon

Dietary Supplements

• Ginseng, American / Asian / Tienchi

• Andrographis• Ashwagandha

• Bacopa• Banaba• Black cohosh• Black pepper• Boswellia

• Centella asiatica• Chamomile• Chinese Salvia• Green tea • ……….

• Witch Hazel• Psyllium• Digitalis• Rauwolfia• Cascara Sagrada• Senna

• Aloe• Plantago• Belladonna• Opium• Myrrh

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USP Powdered Decaffeinated Green Tea Extract –Dietary Supplement monograph

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Monograph title (Nomenclature guidelines)

Definition: botanical characteristics of the plant (genus, species, variety, chemotype), parts of the plants

Identity: macroscopical and microscopical characterization, phytochemical characteristics, profile of the constituents

Strength and Composition: constituents with known activity or markers, toxic constituents (identity, assay, limit tests)

Contaminants (microbial levels, aflatoxins, heavy metals, residues of pre-/post-harvest chemical treatments such as pesticides, fumigants)

Labeling

USP Specifications for botanical ingredients

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AccuracyPrecisionSpecificityLoD / LoQLinearityRobustness

The Science of the Standards

Method Validation criteria

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Monograph Specifications

Consistency with

21CFR111–Identity–Purity–Strength–Composition–Absence of Contaminants

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USP Powdered Ginkgo Extract

• Identification: HPTLC and HPLC tests for the ratio and relative abundance of the flavonol glycosides and terpene lactones.

• Composition: Contents of flavonol glycosides (22% - 27%); terpene lactones(5.4% - 12.0%); bilobalide (2.6% - 5.8%).

• Limits for contaminants: Pesticide residues; elemental impurities; microbial load; Limit of residual solvents.

• Specific tests: Limits for rutin and quercetin; Limits for Ginkgolic acid.

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Complementary tests in Public Standards

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USP General Chapters

Specific for Dietary Supplements:Microbial Enumeration Tests, Nutritional and Dietary Supplements

Microbiological Procedures for Absence of Specified Microorganisms, Nutritional and Dietary Supplements

Microbiological Attributes of Non-sterile Nutritional and Dietary Supplements

Disintegration and Dissolution of Dietary Supplements

Weight Variation of Dietary Supplements

Elemental Contaminants in Dietary Supplements

Detection of Irradiated Dietary supplements

Screening Methods for Undeclared Drugs and Drug analogs

Manufacturing Practices for Dietary Supplements

<2021>

<2022>

<2232>

<2040>

<2091>

<2750>

<2250>

<2251>

<2023>

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USP General Chapters

Non-specific for Dietary Supplements:

<467>

<561>

<563>

<621>

HPTLC

Residual Solvents

Articles of Botanical Origin

Identification of Articles of Botanical Origin

Chromatography

<203>

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Outline USP’s public standard-setting process

Botanical drugs and dietary supplements – quality requirements

Unique challenges and complexities of botanical ingredients

Emerging topics in botanical quality controls

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Specifications for Contaminants

• Limits for pesticide residues ARTICLES OF BOTANICAL ORIGIN <561>: Meets the requirements

• MICROBIAL ENUMERATION TESTS ⟨2021⟩:

• total bacterial count NMT 105 cfu/g,

• the total combined molds and yeasts count NMT 103 cfu/g

• the bile-tolerant Gram-negative bacterial count NMT 103 cfu/g

• ABSENCE OF SPECIFIED MICROORGANISMS ⟨2022⟩: absence of Salmonella species and Escherichia coli.

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<561> Articles of Botanical Origin• For products marketed in U.S. as foods, including dietary supplements,

<561> requires compliance to EPA (40 CFR 180) and FDA action levels (21 CFR 109; 21 CFR 509)

• Specifications in <561> are applicable to botanical drugs (e.g., psyllium husk), but not dietary supplements in U.S. (even for the same ingredient)

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• The MRLs in <561> are based on WHO-FAO ADIs, but are limited to the 90th percentile of the pesticide levels found on the herbs of commerce, i.e., readily accomplished under GACP

• USP compendial approach sets limits based on risk, and does not set not crop-specific limits

• USP <561> MRLs are harmonized with those of Ph. Eur.

• EPA MRLs are based on a submission from a pesticide manufacturer for intended uses of the pest control product on specific crops

USP Limits for Pesticide Contaminants

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Pesticide Contamination in Botanical IngredientsThe Challenge:

EPA established tolerances are plant/pesticide specific

Unintentional pesticide contamination (point-source or non-point-source) due to environmental conditions is ubiquitous

Zero-tolerance limit exists for any residue without specified level

Zero tolerance is not useful for making safety based decisions –new technologies go to ppb levels

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Outline USP’s public standard-setting process

Botanical drugs and dietary supplements – quality requirements

Unique challenges and complexities of botanical ingredients

Emerging topics in botanical quality controls

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Emerging Technologies

DNA-based ID

NMR

Chemometrics

Digital standards and Databases

Non-targeted methods

Metabolomics

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DNA-based methods are useful for botanical ingredient ID– High degree of specificity and sensitivity

– Can distinguish closely related or morphologically similar species

Considerations for DNA-based identification

DNA-based methods are not suitable as the sole basis for ID

– May not be suitable for botanical extracts, unless validated

– False negative results from processed ingredients or due to interferences from the matrix

– False positive results from foreign organic matter naturally occurring in the plant material at low but allowable levels (NMT 2%)

– No guarantee of appropriate Good Agricultural Practices

– May be fooled by deliberate addition of small amounts of raw material

Suitable as an orthogonal test which measures a unique attribute

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DNA Methods for Botanical Identification

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min0 10 20 30 40 50 60 70

mAU

0

20

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100

DAD1 A, Sig=203,16 Ref=360,100 (YITAO\COMPARE\RS1.D)

Rg1Re

Rb1

RcRb2

Rd

min0 10 20 30 40 50 60 70

mAU

0

25

50

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100

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DAD1 A, Sig=203,16 Ref=360,100 (G:\2D(1)~1.D)

Rd

Rb2

Rb2

Re

Rg1

N-R1

min0 10 20 30 40 50 60 70

mAU

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DAD1 A, Sig=203,16 Ref=360,100 (HUPING~2\XY090316.D)

Rg1

ReRb1

RcRb2

Rd

Asian Ginseng

American Ginseng

Notoginseng Rb1

Unique species identifiers

Rf

F11

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HPTLC-based ID

← Rg1

← R1 ← Re ← Rd

← Rb1

← Rg1

← ReRf →

←Rd

← Rc← Rb2

↖ Ro/Rb1

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Polymerase Chain Reaction (PCR) Method

Step 1: Extract DNAStep 2: Amplify with species specific primers Step 3: Run gel electrophoresis and look for specific bands

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Species Specific Primer Design Strategy

Sequence variations

100-200 base pairs, optimal

18-30 base pair, GC content between 40-60%

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Learnings

Pilot studies on species-specific test methods using authenticated and commercial samples demonstrate ability to discriminate; further method development, optimization and validation is still needed.

The studies demonstrate value of orthogonal methods for identification

Orthogonal tests increase confidence on identity based on unique attributes

OOS investigation protocols are needed to address false negative tests due to matrix (such as red ginseng or extracts) which impact DNA extraction or false positives due to contamination

Sequence verification of amplicons using Sanger and NGS as appropriate

Optimization of nucleic acid extraction

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www.usppf.com/

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The criteria for positive and negative control species In silico design of the primers with specificity as an attribute

• Available genome sequence databases, their limitations Validation criteria for species-specific identification

• Controls to identify interspecies variability and avoid unintended target amplification • Optimization of amplification conditions • Criteria for repeatability and reproducibility (multi-lab studies) • criteria and tools for sequence matching, where used

Verification of the methods • System suitability controls including QC for DNA extraction and quantification, • Matrix related challenges such as extracts, leaf versus bark, etc• Use of reference standards for comparison – reference raw material and whole genomic DNA

Acceptance criteria • Controls for false positive non-specific amplification and false negative no amplification outcomes

Brief description of available methods and technologies for detection Use of orthogonal methods Out of Spec investigations

Proposed revision for <563>

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Final Remarks

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The Value of Public Standards

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Provides scientific basis for decision making

Ensures a consistent approach to quality

Useful for monitoring of counterfeit and substandard products and quality

Appropriate titles Useful definitions Validated methods Established limits

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USP Botanical Priorities

Central to USP’s achievements are the contributions of countless professionals, who volunteer their time and knowledge in USP’s Council of Experts and Expert Committees and Panels.

Our Call for Candidates is now open.

Join other motivated colleagues to help us set the standards that make it possible for 2 billion people around the world to have access to quality medicines, foods and dietary supplements.

Contact us at USPVolunteers@usp.org

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Global Supply Chain - The Role for Public Standards

Common standard for both buyers and sellers (basis of

contractual agreements)

Methods must be reliable enough to ensure that buyers and sellers arrive at the same

value

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