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Quality Assurance Systems in Medicinal Plant Production: GACP/ISSC-MAP/HACCP/GMP Chlodwig M. FRANZ University of Veterinary Medicine Vienna/A
Quality Assurance Systems in Medicinal Plant Production :
GACP/ISSC-MAP/HACCP/GMP
Chlodwig M. FRANZ
University of Veterinary Medicine Vienna/A
Where does the raw material come from ?Collection / Wild-crafting
or systematic cultivation
2
Endangered Medicinal Plants
3
Control of Starting Materials(Raw Material of Plant Origin)
Origin of the Starting Material with respectiveDocumentation
Scientific name,variety, chemotype,
plant part, preparation
Content of active substances/
markers
Contaminations(Microorganisms, Pesticides,Heavy Metals, Radioactivity)
Identity - Purity - Quality
4
Possible solutionsPossible solutionsPossible solutionsPossible solutions::::
•Sustainable useof natural resources of MAPs
•Domestication / Introduction into
Cultivation of
endangered species.
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Good Medicinal Plant Practice GMPP
ICS UNIDO - S. S. Handa, Trieste July 2007
GCP GAP
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GA/C/PGuidelines / Directives:EUROPAM / EHGA,
EM(e)A, WHO, Different countries
(e.g. China, Canada)
Hazard Analysis of CriticalControl Points (HACCP)
for Foodstuff (herbal teas, plant food supplements,
spices)
Good Manufacturing Practice(GMP)
for Herbal MedicinalProducts
ISSC-MAP
Quality Assurance Systems…
7
Influence of genetic, environmental and technological factors on the quality and safety of herbs and botanicals
Dust
MoistureInsect
Pollution
Pesticides
Fertilization
Insect
Micotoxins
Bacteria
HerbsPlan
t
Processing-storage
Finished Vegetal Substance
Heavy Metal, Pesticide
Soil
Contaminations :Pests , diseasesAgrochemicalsHeavy metals
Other qualityfactors , e.g. weeds,microorganisms
Inhomogeneitywithin a batch
Inhomogeneitybatch to batch
Differencesbetween years
Individualgeneticvariability
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Main influences on quality of starting materials
Genotype Environment
Plant Part Development Stage
Phenotype =Quality
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Variety testing of medicinal plants
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Effect of Day Lengthon Origanum syriacum
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Echinacea: field cultivation on plastic mulch
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Salvia officinalis affected by mildew
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Pharmacopoea Europaea ,2.8.13. Pesticide -ResiduesSubstance Limit
(mg/kg)
• Alachlor 0,02
• Aldrin und Dieldrin (deren Summe) 0,05
• Azinphos-methyl 1,0
• Brompropylat 3,0
• Chlordan (Summe aus cis-, trans- und
• Oxychlordan) 0,05
• Chlorfenvinphos (Clofenvinfos) 0,5
• Chlorpyrifos 0,2
• Chlorpyrifos-methyl 0,1
• Cypermethrin (und Isomere) 1,0
• DDT (Summe aus p,p‘-DDT, o,p‘-DDT,
• p,p‘-DDE und p,p‘-TDE) (Clofenotan) 1,0
• Delamethrin 0,5
• Diazinon (Dimpylat) 0,5
• a.s.o. … 14
0
0,01
0,02
0,03
0,04
0,05
0,06
0,07
GP AG Tot. Sugars Sucrose
Seasonal Variation of Amarogentine , Gentiopicrosideand Sugars in Gentiana lutea Roots
Franz et al., 1985
March April Mai June July Aug. Sept. Oct.
%AG
2,0
4,0
6,0
8,0
%GP
3,5
4,0
4,5
5,0
% Tot. Sug. % Sucr
0,5
1,0
1,5
2,0
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Echinacea purpurea harvest
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Lavandulae flos /aetheroliumLavandula officinalis and/or x hybrida
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Manual picking of chamomile flowersin Egypt
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Chamomile: field with weeds
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Large scale chamomile harvesting
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Chamomile : flower-stem -separation
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Belt Dryer for herbs
Quality of the Product?? ����
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Dandelion : washing andseparation of herb / roots
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Bilder: M. Rendlen
Pepper peeling (production of White Pepper) in Ind onesia
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Appropriate drying of herbs ?
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27
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Drying of roots asHMP starting Material (!!)In Centroamerica
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Bild: M. Rendlen
Open-Air Drying of Red Pepper
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Red Pepper drying: moulds, aflatoxines?
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Slide 22European Seminar, 19 November 2004, Brussels
Moulds forming Mycotoxins
Micro-organism Mycotoxin
Aspergillus spec. Aflatoxin B1, B2, G1, G2,
Metabolite in mammals Aflatoxin M1
Aspergillus spec., Penicillium spec. Patulin
Ochratoxin A
Fusarium spec. Fumonisin
Zearalenon
Trichothecenes:
- Deoxynivalenol and Nivalenol
- T2 Toxin and HT2 Toxin
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Slide 14European Seminar, 19 November 2004, Brussels
Microbiological Contamination of Herbal Drugs
Salmonella96,7 %
3,3 %
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
negativ positiv
Count per 25 g
n sam
ples
Samples tested: 17.833
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Desinfestation with liquid nitrogen (cold desinfestation ) 34
Slide 26European Seminar, 19 November 2004, Brussels
Desinfestation and Storage of Herbal Raw Materials
CARVEX CO2 Desinfestation
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Dried peppermint leaves
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Guidelines „Good Agricultural Practice (GAP)“ for Medicinal and Aromatic Plants
StepwiseQuality Control
Starting MaterialSpecies,Variety, CultivarChemotype,Resistancesspec. characters(e.g. „usability value“)
CultivationGrowing site, Crop rotation,Production techniqueand Maintenance,Fertilization, Plant Protection,spec. Methods (e.g. organicproduction), Harvest time andtechnique
SafetyPreventionagainst Intoxications
StorageStorehouse Conditions, Packaging
Post Harvest HandlingTransport from field,Washing, drying,Processing
FRANZ 199937
Milestones IGuidelines Good Agricultural Practice for MAP‘s
1975 WHO Good Manufacturing Practice for Pharmaceuticals(GMP), Off. Rec. WHO No. 226 (1975)
1983 ISHS Symposium Angers, Start of the GAP-discussion1985 EHIA Guidelines to Good Agricultural Practice for Herbal
Infusion Raw Materials1986 UNIDO Guidelines for the Supply of Medicinal Plants as
Raw Materials for Processed Products1988 ISHS Symposium Novi Sad, basic statement on GAP
guidelines
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Milestones IIGuidelines Good Agricultural Practice for MAP‘s
1989 Way Bill (batch documentation) for MAP’s and Herbal Drugs: Newsletter of MAP 1989 No. 2, p. 15
1991 Discussion Paper: Guidelines for Integrated Plant Production of MAP’s (Drogenreport, Special Edition)
1998 EU Directive on Starting Materials for Medicinal Products; EHIA, AESGP, ESCOP, EUROPAM: involved in GAP Guidelines for herbal medicinal products (and aromatic plants)
2003 WHO Guidelines for GACP for medicinal plants2006 EMeA GACP Guidelines for Herbal Materials2010 Version 8.0 of the EUROPAM GACP-MAP Guidelines
(actually under revision!)
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Guidelines for Good Agricultural and Wild Collection Practice (GAP) of Medicinal and Aromatic Plants
1. General Introduction: Scope, Environment, Cultivation/Wild Collection
Biodiversity, Endangered Species, Confusion/Adulteration, Quality, Hygiene,Realisation
2. Personnel and Facilities: Education , Hygiene, Health Care
and Protection, Social Welfare, Conformity with other (EU/national) Regulations
3. Seeds an Propagation Material: Identity , Variety, Chemotype, Origin, Traceability;
Purity, Germination, free of Pests etc.
4. Cultivation: Mode of Cultivation: Conventional / OrganicSoil and Fertilization, Contamination, Irrigation, Crop Maintenance and PlantProtection, Qualified Staff; Documentation; Person in charge for Conformity
5. Harvest / Wild Collection: Harvest time, Equipment and Devices,
Admixtures, Purity, Damaging, Containers, Protection against Impurities andEnvironmental Influences; Transport to Post-Harvest Facilities; Person in charge
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Guidelines for Good Agricultural and Wild Collection Practice (GAP) of Medicinal and Aromatic Plants6. Primary Processing
washing, drying, freezing, distillingbuildings: purity, protection against weather conditions, microorganisms, pests, rodents, birdsprocessing equipment: material, purity
7. Packagingpurity and labelling
8. Storage and Transportwarehouse, ev. cold store,purity and protection against contaminationseparate storage conventional/organic products
cross contamination (espec. essential oils)
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9. Equipmentmachinery, equipment and its care
10. Documentation of all stepsfield recordsway bill (batch documentation)analyse-reportsaudit-reports
11. Quality Assurance
agreements between supplier and customer
12. Self Inspectionmonitoring the implementation of GA(C)Pby a competent person of the farm / company
Guidelines for Good Agricultural and Wild Collection Practice (GAP) of Medicinal and Aromatic Plants
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GACP Guidelines: EUROPAM EMeA WHO
• General Introduction - General Introduction - General Introduction
• Personnel and Facilities - Quality Assurance - GAP for medicinal plants
• Seeds/Propagat. Material - Personnel and Education
• Cultivation - Buildings and Facilities
• Harvest/Wild Collection - Equipment - GCP for medicinal plants
• Primary Processing - Documentation
• Packaging - Seeds/Prop. Material
• Storage and Transport - Cultivation / Collection
• Equipment - Harvest - Common techn. Aspects
• Documentation - Primary Processing
• Quality Assurance - Packaging
• Self Inspection - Storage and Distribution - Other relevant issues43
GA/C/PGuidelines / Directives:EUROPAM / EHGA,
EM(e)A, WHO, Different countries
(e.g. China, Canada)
Hazard Analysis of CriticalControl Points (HACCP)
for Foodstuff (herbal teas, plant food supplements, spices)
Good Manufacturing Practice(GMP)
for Herbal Medicinal Products
ISSC-MAP
Quality Assurance Systems…
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Good Wild Crafting Practice –Good Field Collection Practice
• „... Wild growing more convenient than cultivation“• (e.g. small quantities, high costs of cultivation, ...)
• Sustainability • Certification• Conservation • ‘ISSC-MAP’
(WWF/TRAFFIC)
• Quality ?
„Certified Wild Crafting of Medicinal Plants?“45
Wild Collection of Plants :very „natural“ – including Diversity
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Petasites hybridus (butter bur)
Tussilago farfara (coltsfoot) 47
24424261
98
147
236
378384
195185
175165
155145
135125
115105
9585
7565
5545
3525
155
500
400
300
200
100
0
Positive and negative Substances in Petasites
Pyrrolizidine-Alkaloids: liver toxic !
0
5
10
15
20
25
30
35
40
45
50
Neo-S-Petasin
S-Petasin
Neo-Petasin
Petasin
Petasines: anti-allergenic
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Invasion of Senecio species and other toxic weeds
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Gentiana lutea and otherGentiana sp. (bitter) vs.Veratrum album (toxic!)
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These results show:
• that occasionally herbal drugs are adulterated with foreign or even toxic plants. This applies especially to plants from collection in wild habitats, where confusion with similar plants as well as poorly qualified personnel presents a risk for the quality of the herbal drug,
• that especially the identity and purity of herbal TC(M) drugs is problematic and
• that regular tests for confusions/admixtures/adulterations
on one side,
• but also on heavy metals, pesticides, mycotoxins and microbiological counts are required
to get appropriate quality information.
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International Standard for
Sustainable Wild Collection of Medicinal and Aromatic Plants
(ISSC-MAP)
� Most MAP species are now – and will continue to be – wild collected!
� Cultivation cannot be the principal solution to over-harvesting!
Ca. 900 MAP species are commercially cultivated.
Photo: Yan Zhijian
Estimation of wild collection• (70)-90% in terms of species numbers• 50-(70%) in terms of quantity
Production of MAPs
About 15,000 medicinal plant species may be threate ned to some degree world-wide (IUCN).Make wild collection sustainable now !
Photo: I. Goehler
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Challenges for a Standard on Sustainable Wild Collection of MAP
• Unique circumstances of ecology, habitat, and pressures on resource for each species
• Harvesting techniques: Questions about “how to” collect wild MAP sustainably
• Uncertainty about annual sustained yield
Photo: K. Duerbeck
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Challenges for a Standard on Sustainable Wild Collection of MAP
• Large number of products, uses, and markets
• Proliferation of labels and claims regarding sustainability without means for validation
• Long and complex supply chains – difficult to trace product back to its source
??
Management Plans for Species and Regions
Devils ClawNamibia
ArnicaRomania
BearberryRussia
RatanhiaPeru
Guidelines for MAP Conservation,
Production, Quality Control (= general recommendations)
WHOGACP
WHO IUCN WWFConservation
Guideline
The missing link:set of rules to define, implement, and evaluate good management practices
ISSC-MAP
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Existing Frameworks & Gaps
Ecosystem Managemente.g. Forest – FSC
Organic Agriculture – IFOAM, Demeter
Health and Safetye.g. GACP – AHPA,
EMeA, WHO
Equitye.g. Fair trade – FLOAccess and Benefit
Sharing regime, FairWild
Species Conservation& Sustainable Use
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Legal Adoption& Policy
CITES
Development 2004-2006 Imple mentation 2007-….
Process
Drafting Voluntary Codesof Practice
Consultation
ResourceManagement
Certification
Development Cooperation
Information &Training
ISSC-MAP
Plant Product
People &Politics
Testing
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ISSC-MAP – Purpose
To ensure the continued use and long-term survival
of medicinal and aromatic plant (MAP) species and populations in their habitats, while respecting the traditions, cultures and livelihoods of all stakeholders.
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ISSC-MAP – Objectives
• To provide a framework of principles and criteria that can be applied to the management of MAP species and their ecosystems
• To provide guidance for management planning
• To serve as a basis for monitoring and reporting, and
• To recommend requirements for certification of sustainable wild collection of MAPs.
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ISSC-MAP Version 1.0 (2007): 3 Levels
6 Principles
18 Criteria
100+ Indicators
• Press launch BioFach, Nuremburg, Germany Febr 07
• 1st release in North America at Natural Products Expo West, March 07
• Available online at www.floraweb.de/map-pro
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ISSC-MAP Version 1.0: 6 Principles
Maintaining Wild Map ResourcesMaintaining Wild Map Resources
Preventing Negative Environmental ImpactsPreventing Negative Environmental Impacts
Respecting Customary RightsRespecting Customary Rights
Applying Responsible Management PracticesApplying Responsible Management Practices
Applying Responsible Business PracticesApplying Responsible Business Practices
Compliance with Laws, Regulations, and AgreementsCompliance with Laws, Regulations, and Agreements
Wild collection and conservation requirements
Legal and ethical requirements
Management and business practices
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Who benefits from a widely accepted, credible standard?• Industry ���� sustainable resource use and corporate
social and environmental responsibility
• Resource managers ���� guidelines for MAP protection, harvest, and monitoring
• Collectors ���� insurance against resource and market failures
• Consumers ���� reliability of claims about ecological sustainability and fair trade
• Species and habitats ���� maintain biodiversity
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Quality Management
Quality Assurance Quality Control
GAP / ISSC-MAPHACCP / GMP
GLP
Factors influencing
Quality
Starting MaterialProcessing
Final ProductsStaff
AnalyticalMethods
Documentation of all Fields and Steps 64
GA/C/PGuidelines / Directives:EUROPAM / EHGA,
EM(e)A, WHO, Different countries
(e.g. China, Canada)
Hazard Analysis of CriticalControl Points (HACCP)for Foodstuff (herbal teas,
plant food supplements, spices)
Good Manufacturing Practice(GMP)
for Herbal Medicinal Products
ISSC-MAP
Quality Assurance Systems…
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Worldwide uniform
Hygiene Rules
Consumers Health
Protection byRisk Assessment
Safety concept forProduction , Processing
(treating) andMarketing of Foodstuff
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Dandelion : washing andseparation of herb / roots
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Bilder: M. Rendlen
Pepper peeling (production of White Pepper) in Indonesia
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Appropriate drying of herbs ?
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Assembling a HACCP Team
Product Description
Intended Use of the Product
Flow Diagram / Process Description
Internal Checking of the Flow Diagram
Risk Assessment andControl Measures
Identification of the CCPs
Fixation of the Limits for each CCP
Development of a Monitoring System for each CCP
Establishing of Correction Measures
Establishing of Verification Methods
Documentation, etc. 71
HACCP Decision TreeDo Control Measures
for Risks exist?
no
no no
no
no
yes
yes
yes
yes
yes
no
Control due to risks atthat point necessary?
Modify steps,procedures orproduct
Next processstep
Risk reduced bythis step?
Inacceptable riskor contamination?
Risk reduced by afurther process step?
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GA/C/PGuidelines / Directives:EUROPAM / EHGA,
EM(e)A, WHO, Different countries
(e.g. China, Canada)
Hazard Analysis of CriticalControl Points (HACCP)for Foodstuff (herbal teas,
plant food supplements, spices)
Good Manufacturing Practice(GMP)
for Herbal Medicinal Products
ISSC-MAP
Quality Assurance Systems…
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GMP for Active Pharmaceutical Ingredients(Internat. Version)
• API extracted from plant sources: Collection, cuttingand initial extraction: GAP
• Herbal Extracts used as API: same as above• API consisting of comminuted/powdered herbs: same
as above
• Introduction of API Starting Material into Process & furtherExtraction : GMP
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New Version Annex 7 (in force 01.09.2009)New Version Annex 7 (in force 01.09.2009)
Activity Good Agricultural
and Collection Practice
Part II of the GMP Guide
Part I of the GMP Guide
Collection, Cultivation and harvesting of plants, algae, fungi and lichens, and collection of exudates
Cutting and drying of plants, algae, fungi, lichens and exudates ‘on farm’ only!
Expression from plants and Distillation *
Comminution, processing of exudates, extraction from plants, fractionation, purification, concentration or fermentation of herbal substances substances
Further processing into a dosage form including packaging as a medicinal product
Bundesverband der Arzneimittel-Hersteller1
* If necessarily integral part of harvesting, GACP is accepted – following GMP!
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Premises , Equipment etc.
• Storage areas: separate and protected (against insects, animals,… well
aerated, clean, protection against high humidity, temperatur, light
• Production area: protected against dust (especially at manufacturing;
avoid cross-contamination!)
• Equipment: compatible with the extraction solvent
• Documentation: Specifications for starting materials in compliance with GACP,
incl. nomenclature, residues...
• Processing Instructions – Quality Control – Sampling: in compliance
with PharmEur and GMP
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Quality of Botanical Preparations
Requirements for the Manufacturing of Extracts
FSE (Food Supplements Europe) October 2014
HDP‘s: Herbal Dietary Products (= Food Supplements),HMP‘s: Herbal Medicinal Products
Plants as sources of Botanicals
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Quality Management
Quality Assurance Quality Control
GACPHACCP / GMP
GLP
Factors influencing
Quality
Starting MaterialProcessing
Final ProductsStaff
AnalyticalMethods
Documentation of all Fields and Steps 79
…thank youfor yourinterest…!
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