TimRoss,May2017 UCLACenterforEast-WestMedicine

Addressingthelackofobjectivestandards

forthequalitycontrolofChineseherbalmedicines

Iexperiencegreattrepidationwhenshoppingforherbalproducts.Iknowthereisno

standardforobjectivequalitycontrol.Consequently,thebagsandbottlesofherbswefindon

theconsumermarketcanhaveanalmostlimitlesscomposition.Atbest,theplantscontributing

materialtothecompositionoftheherbalproductareallwellidentifiedbutbeyondthatallbets

areoff.Intheiroutlineofgoodmanufacturingpractices,theFDAemphasizes“identity,purity,

strengthandcomposition”astheguidingprinciplesofherbalqualityassessmentandquality

control(FDA,2009).Unfortunately,theseprinciplesareappliedatthemanufacturersdiscretion

andthereisnonationalstandard.Inpracticethisleadstoextremevariationinthe

concentrationsoftheimportantactiveingredientswithintheseherbalproducts.Thisextreme

variationis,inmyopinion,thebiggestobstacletotheefficaciousapplicationofChinese

medicinalherbsoutsideofpractitionerskill.

Adventuresinqualitycontrol–TheArtemisiadebacleof2016

Intheinterestoffulldisclosure,Iamaclinician,QA/QCprofessionalaswellasagrowerof

Chineseherbsdomestically(RossTJ,2016).Ihavewornthehatsofallthemajorplayersinthis

relationshipbetweengrowers,brokers,manufacturers,clinicians,retailersandconsumers.The

strongestforcedeterminingthemannerofrelationbetweenalloftheseactorsisprofit.Iwould

saythatsafetyisalsoaconcern.Unfortunately,efficacywouldappeartobeanafterthought.

Currently,theChineseherbQingHao/HerbaArtemisiaannuaanditsmajoractive

constituentArtemisininhaveacquiredgreatrenown.Itisinhighdemandandatmyplaceof

employasaQA/QCprofessionalwehadahugeorderforaformulacontainingArtemisiaannua.

Wewerehavingtroublefindinganythatmetourrequirementofdomesticproduction.We

couldonlyfindtwolargebatchesofdriedArtemisiaannuafromthepreviousyear’sharvest.

Bothwereabout90%stemmaterialbyweight.(TheWorldHealthOrganizationrecommends

thatstembelessthan10%ofthetotalweight(WHO,2006).)Neithershowedthepresenceof

anyflowersorflowerbuds.

ArtemisiaAnnua,PacificBotanicals,2015

Artemisiaannua,TheWheelHerbFarm,2015

Artemisiaannua,representativesample

Clearlythismaterialdidnotsatisfythefundamentalrequirementsforthemedicinalmaterial

QingHaoasstatedintheChinesePharmacopoeia(“Harvestinautumnduringthetimeoffull

bloom,removetheoldstem”)butitwasArtemisiaannua(ChinesePharmacopoeia

Commission,2010).Additionally,itwasfreeofpesticides,heavymetalsandanyother

adulteration.Attheveryleastitwassafe.Itcouldsatisfythebasicrequirementssetforthby

theFDAwithinthecurrentGMPguidelines.

Myadvicewastoseparatethestemfromtheleaf,sendthestembacktothegrowersand

demandthatportionofthecostbereturned.Unfortunately,withoutusingthestemmaterial,

productionwouldnothavebeenabletofulfilltheorder,sothestemmaterialwasusedalong

withtheleaftomakethenecessaryalcoholextracts.Amonetarydecisiontrumpedconcerns

aboutefficacybutthisdecisionwasacceptablewithinthecurrentallowableapplicationsofthe

FDA’sGMPrequirements.

Thetestscurrentlyrequiredtodemonstrate“strengthandcomposition”cannotstopthis

kindofgoalpostshifting.Primarilystrengthandcompositionisdemonstratedbyshowing

conservationofweighttovolumeratioswhichaddresstheamountofherbmaterialpresentin

theproductbutsaynothingabouttheconcentrationofactiveconstituents.

Therearenonationalstandardsforthequalityofherbmaterialsusedindietary

supplements.YourArtemisiaannuacouldbeanywherefromaboutamaximumof1%

artemisinintoaminimumofa100ormoretimeslessthanthat.Asaclinician,howisone

expectedtodosematerialsinareliablewaywhenthebatchtobatchdifferencesinthepotency

ofthemedicinescanbeinthe10s,100sorevenhigher?

InthecaseofArtemisiaannua,weknowthatthemajoractiveconstituentisfoundinthe

flowersandleaves.Themedicinalmaterialshouldbeandhasbeentraditionallylimitedtothe

leavesandflowers.IthasbeenshownviamodernanalyticalmethodsthatArtemisinin

concentrationreachesitspeaksaroundtheperiodoffullbloom(Baraldietal.,2008).So

percentflowerheadwouldbeadecentmeasureforthequalityofthemedicinalmaterial

derivedfromArtemisiaannua.Isuggestthatcontrollingforpercentflowerbudbyweightand

percentstemmaterialbyweightwouldbeadequate.Thisovercomestheprimaryobjection

fromthemanufacturers(expense)andprovidesatimetestedmethodtoinsuretheefficacyof

themedicinalmaterial.Ideallywewouldexpandthequalityrequirementsforeveryherbina

similarway.

Traditionalqualityassessmentofrootmedicinals

Historically,organolepticmethodsprimarilyfocusingontheevaluationofplainlyobvious

macroscopicfeatureshasbeenthemainmethodforthequalitycontrolofChinesemedical

herbmaterial(Zhao,Liang,&Ping,2011).ThemostfamousandcommonChineseherbssuchas

RenShen/Panaxginseng,HuangQi/Astragalusmembranaceus,GanCao/Glycyrrhizauralensis,

DangGui/AngelicasinensisandBaiShao/Paeoniaealbahavealltraditionallybeengradedfor

qualityaccordingtodiameterandlength.Potencyhasalwaysbeenassociatedwithhigher

gradeandthereisincreasingamountsofanalyticalevidencetosupportthisconclusion(Z.

Wang,Wang,&Huang,2014).

Itisimportanttorankrootmaterialsbygradetoallowforsomebasicqualityassessmentto

bemade.Ingeneral,weseeherbbrokersmovingtocutsthatmakeitincreasinglydifficultto

applytraditionalmethodsofqualityassessmentthatrequirewholerootsortransverse

sections.Itismyconjecturethatthistrendisaconsciousmovetohidetheevershrinkingroot

length,diameterandcultivationlengthoftheseimportantrootmedicinals.Traditionallythe

rootofAstragalusmembranaceuswascollectedinInnerMongoliaoranearbyaridregionafter

6years.Nowitisoftencultivatedinthemostincongruousclimatesandharvestedafterless

than1year.Needlesstosay,thereisahugedifferenceinthechemicalcompositionofwild

crafted6yearoldrootwhencomparedtoacultivated1yearoldroot(Xin,Ma,Xie,Wang,&

Hou,2015).

BecausethegreatmajorityofcliniciansandconsumersintheUShavenoideawhatquality

specificationstheyshouldlookforinmedicinalmaterials,weletmaterialonthemarket

withoutgradingitinanywayandatypeoffalseequivalencyisestablished.Whenthegrowers

realizedthemarketcan’ttellthedifferencebetween3,2and1-year-oldroots,theystarted

harvestingeverythinginthefirstyear.(Thisisabitofanexaggerationbutitisimpossibleto

ignorethesteadydeclineincultivationlengthamongcommonmedicinalssuchasHuang

Qin/Scutellariabaicalnesis,DangShen/CodonopsispilosulaandHuangQi/Astraglus

membranaceus).Whenwelookatthechemicalfingerprintoftheabovementionedspeciesin

the3rdyearascomparedtothe1styear,thereisnocomparison,theyarehardlyeventhesame

medicinal(RossTJ,2014).Itislikecomparingthemindofamanat10tothemindofthatman

at30.

Weshouldbegintorealizethatefficacyisnotindependentofqualitycontrol.Whenwedo

nothavereproduciblequalitieswithinsomereasonablelimitofprecisionwecannotexpectto

havereproducibleeffects.Attheveryleast,qualityrequirementsneedtobeexpandedto

includethetraditionalmacroscopicmethodsofqualityassessment.

Forexample,HuangQi/Astragalusmembranaceuscanbegradedforqualityaccordingtothe

followingmethod(金世元,2010).

• 1stclassismorethan50cmlong,upperandmiddleportionsaremorethan1.5cmin

diameter,tipdiameterisnotlessthan0.5cm

• 2ndclassismorethan40cmlong,upperandmiddleportionsaremorethan1cmin

diameter,tipdiameterisnotlessthan0.4cm

• 3rdclasshasvariablelength,theupperandmiddleportionsaremorethan0.7cmin

diameter,tipsarenotlessthan0.3cm

Inadditiontothesebroadcriteriathereareothermorenuancedmacroscopicandorganoleptic

featureswhichmustbeconservedincluding–

• Longthickrootpieceswithoutahollowedcenter

• Pliable,tough

• “Goldencup,silversaucer”

• Powdery,fibrousnature

• “Chrysanthemumflowerpattern”

• Beanlikeflavor

IfwelookatarawmaterialspecificationsheetthatisdesignedtomeettheFDAGMP

requirementswhatwewouldlikelyfindisinfoontheappearanceofthemedicinalaswhole

root,cross-sectionandpowderaswellasinfoonhowtoaccuratelydifferentiateAstagalus

membranaceusfromitscommonadulterantHedysarumpolybtrys.Whatishardertoidentifyis

thematerialthatisinformingusonhowwemightmeasureandcontrolthequalityofthis

material.Thismeasureandcontrolisoftenlefttoasubjectiveappreciationofodorandtaste

andtheobjectiveconsiderationoftheamountofextraneousmaterialpresent(adulteration).

Thisisverydifferentfromthetraditionalnotionsofqualitycontroldescribedabovewhichcould

alsobeexpandedtoincluderequirementsforgrowingregion,cultivationlength,harvesttime

andprocessingmethod.

EnsuringQuality–Education,Regulation,Implementation

WhatIampushingforisthereintroductionoftheroleofpharmacognosyintothepractice

ofChineseherbalQA/QC.Thiswillrequireincreasingeducationaldemandsplacedonstudents

andclinicians,anincreasingcomplexregulatoryapparatusandthecomplianceoftheherb

growersandherbalproductsmanufacturers.ThismodificationtothecurrentpracticeofQA/QC

willrequirea3prongedapproach.

1. CreatingthebroadlyacceptedQA/QCmonographsforeachherbbyacademicsand

cliniciansfromtheUSinconjunctionwithexpertsinpharmacognosyfromChina.

Theprimaryfocuswillbedevelopinganuancedandcosteffectivecombinationof

organoleptictests,combinedwithanalyticalchemicaltestswhennecessary,specifictoeach

individualherbthatwouldallowforthequalitycontrolofthemedicinalpropertiesofeachherb

withinarangethatwouldensureclinicalefficacy.

2. Disseminatingthisinformationtoclinicians,manufacturersandconsumers.

Atthispointintime,theinformationrequiredforclinicians,manufacturersandconsumers

tomakeexpertjudgmentsaboutthequalityofChineseherbmaterialsisleftbehindthe

forbiddingwallofChineseliteracy.Movingforward,itwillbenecessarytotranslatethis

materialandpromoteitsdisseminationtorelevantconsumers.Iwouldheavilyrecommendthe

additionofasingle4unitclasstothecorecurriculumrequiredfortheMaster’sdegreeinEast

AsianMedicineofferedintheUS.

3. Enforcingthesestandardswithinthemarketplacebyincreasingtheburdenof

regulationplaceduponherbgrowers,wholesalers,herbalproductsmanufacturers,and

herbretailers

Inevitablyalloftheabovewillonlycometofruitionifbackedupbyincreasedregulations.

TheFDApolicyontheGMPofdietarysupplements,atleastasitisrelatedtoChinesemedicinal

herbsmustchange.Wemustseriouslyconsiderthewisdomofcontinuingtolumpmedicinal

herbsinwith“dietarysupplements’.Icouldseeaseparationinto2tiersbasedonquality

regulations.Tier1beingfor“dietarysupplements”andrequiringonlythecurrentsetofteststo

ensureforidentityandlackofadulteration.Tier2beingfor“medicinalherbs”andrequiring

somesetofteststoestablishthequalityofthemedicinalmaterialasbeing“therapeuticgrade”.

Themostcommonlyignoredsubjectwithinthediscussionaboutthesafeandeffectiveuse

ofChineseherbalmedicinesisthequestionofherbquality.Itisnotsafeforpeoplewith

legitimateillnesstoseekcarethatinvolvestheapplicationofineffectivemedicineslackingthe

necessaryconstituentconcentrationstobetherapeuticallyviable.Thisfrequentfailureof

cliniciansandconsumerstogetgoodresultswiththeirherbaltherapiesduetoaninabilityto

identifyqualitymedicinalsalsoleadstoadiminishingconfidenceintheefficacyofChinese

medicinalherbs.Wemustactstronglytopreventanyfurtherreductioninthequalityofherb

materialweseeonthemarketbyincreasingeducationandregulatoryrequirementsinthis

area.

References:

FDA.(2009).GMP21CFR111.

"(1)Youmustselectoneormoreestablishedspecificationsforidentity,purity,strength,

composition,andthelimitsonthosetypesofcontaminationthatmayadulterateorthat

mayleadtoadulterationofthedietarysupplementthat,iftestedorexaminedonthe

finishedbatchesofthedietarysupplement,wouldverifythattheproductionandprocess

controlsystemisproducingadietarysupplementthatmeetsallproductspecifications"

Baraldi,R.,Isacchi,B.,Predieri,S.,Marconi,G.,Vincieri,F.F.,&Bilia,A.R.(2008).Distributionof

artemisininandbioactiveflavonoidsfromArtemisiaannuaL.duringplantgrowth.

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https://doi.org/10.1016/j.bse.2007.11.002

ChinesePharmacopoeiaCommission.(2010).PharmacopoeiaofthePeople’sRepublicofChina

(Vols.1–4).ChinaMedicalSciencePress.

RossTJ.(2014).ComparingtheChromatographicFingerprintandAnti-CancerEffectof

ScutellariaSpeciesGrowninNorthAmericatothosegrowninChina.BastyrUniversity.

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final-2b.pdf

RossTJ.(2016).HuangQinqualityassessment-applicationsandobservations.Retrievedfrom

https://www.youtube.com/watch?v=lqdbbctPQhk

Wang,Z.,Wang,D.,&Huang,L.(2014).AnalysisoftheCorrelationbetweenCommodityGrade

andQualityofAngelicasinensisbyDeterminationofActiveCompoundsUsing

UltraperformanceLiquidChromatographyCoupledwithChemometrics.Evidence-Based

ComplementaryandAlternativeMedicine:eCAM,2014,143286.

https://doi.org/10.1155/2014/143286

WHO(Ed.).(2006).WHOmonographongoodagriculturalandcollectionpractices(GACP)for

ArtemisiaannuaL.Geneva:WHO.

Xin,B.,Ma,S.,Xie,J.,Wang,W.,&Hou,J.(2015).[InfluenceofDifferentGrowingYearson

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Zhao,Z.,Liang,Z.,&Ping,G.(2011).MacroscopicidentificationofChinesemedicinalmaterials:

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134(3),556–564.https://doi.org/10.1016/j.jep.2011.01.018

金世元.(2010).金世元中药材传统鉴别经验.北京:中国中医药出版社.