Addressing the lack of objective standards for the …...Tim Ross, May 2017 UCLA Center for...
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Tim Ross, May 2017 UCLA Center for East-West Medicine Addressing the lack of objective standards for the quality control of Chinese herbal medicines I experience great trepidation when shopping for herbal products. I know there is no standard for objective quality control. Consequently, the bags and bottles of herbs we find on the consumer market can have an almost limitless composition. At best, the plants contributing material to the composition of the herbal product are all well identified but beyond that all bets are off. In their outline of good manufacturing practices, the FDA emphasizes “identity, purity, strength and composition” as the guiding principles of herbal quality assessment and quality control (FDA, 2009). Unfortunately, these principles are applied at the manufacturers discretion and there is no national standard. In practice this leads to extreme variation in the concentrations of the important active ingredients within these herbal products. This extreme variation is, in my opinion, the biggest obstacle to the efficacious application of Chinese medicinal herbs outside of practitioner skill. Adventures in quality control – The Artemisia debacle of 2016 In the interest of full disclosure, I am a clinician, QA/QC professional as well as a grower of Chinese herbs domestically (Ross TJ, 2016). I have worn the hats of all the major players in this relationship between growers, brokers, manufacturers, clinicians, retailers and consumers. The
Transcript of Addressing the lack of objective standards for the …...Tim Ross, May 2017 UCLA Center for...
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.
BiochemicalSystematicsandEcology,36(5–6),340–348.
https://doi.org/10.1016/j.bse.2007.11.002
ChinesePharmacopoeiaCommission.(2010).PharmacopoeiaofthePeople’sRepublicofChina
(Vols.1–4).ChinaMedicalSciencePress.
RossTJ.(2014).ComparingtheChromatographicFingerprintandAnti-CancerEffectof
ScutellariaSpeciesGrowninNorthAmericatothosegrowninChina.BastyrUniversity.
Retrievedfromhttps://cultivate3d.files.wordpress.com/2017/05/tim-ross-capstone-
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
AccumulationofFlavonoidsandSaponinsinAstragaliRadix].ZhongYaoCai=
Zhongyaocai=JournalofChineseMedicinalMaterials,38(7),1366–1369.
Zhao,Z.,Liang,Z.,&Ping,G.(2011).MacroscopicidentificationofChinesemedicinalmaterials:
traditionalexperiencesandmodernunderstanding.JournalofEthnopharmacology,
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.
