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Dr. Markus Veit
3.2.S. DRUG SUBSTANCE/DRUG PREPARATION
3.2.S. 1 General Information 3.2.S.1.1 Nomenclature Information on the nomenclature of the herbal substance should be
provided:- Binomial scientific name of plant (genus, species, variety and author),
and chemotype (where applicable)- Parts of the plants- Definition of the herbal substance- Other names (synonyms mentioned in other Pharmacopoeias)- Laboratory code
Dr. Markus Veit
3.2.S. 1 General Information 3.2.S.1.1 NomenclatureInformation on the nomenclature of the herbal preparation should be
provided:- Binomial scientific name of plant (genus, species, variety and author),
and chemotype (where applicable)- Parts of the plants- Definition of the herbal preparation- Ratio of the herbal substance to the herbal preparation- Extraction solvent(s)- Other names (synonyms mentioned in other Pharmacopoeias)- Laboratory code
3.2.S. DRUG SUBSTANCE/DRUG PREPARATION
Dr. Markus Veit
3.2.S.1.2 Structure The following information for herbal substance(s) and herbal
preparation(s) where applicable, should be provided:- Physical form- Description of the constituents with known therapeutic activity or
markers (molecular formula, relative molecular mass, structural formula, including relative and absolute stereochemistry, the molecular formula, and the relative molecular mass).
- Other constituent(s)
3.2.S.1.3 General Properties
3.2.S. DRUG SUBSTANCE/DRUG PREPARATION
Dr. Markus Veit
3.2.S.2 Manufacture 3.2.S.2.1 Manufacturer(s) For herbal substances The name, address, and responsibility of each supplier, including
contractors, and each proposed site or facility involved in production/collection and testing of the herbal substance should be provided, where appropriate.
For herbal preparations The name, address, and responsibility of each manufacturer,
including contractors, and each proposed manufacturing site or facility involved in manufacturing and testing of the herbal preparation should be provided, where appropriate.
3.2.S. DRUG SUBSTANCE/DRUG PREPARATION
Dr. Markus Veit
Produktion Pflanzlicher Arzneimittel
frische Pflanzen Drogen (getrocknet)
Presssäfteselten Extrakte
ArzneiteesDrogen-PulverExtrakte
Fertigarzneimittel in verschiedenen Darreichungsformen und Anwendungsarten
TrocknungLagerungVerpackungTransport
Anbau/Ernte
Folie Dr. Stolte
Dr. Markus Veit
Anbau oder Wildsammlung
Unkontrollierte
BedingungenKontrollierte
Bedingungen
Folie Dr. Stolte
Dr. Markus Veit
Einheitliches Pflanzenmaterial kann aus Wildsammlungen nicht erhalten werden, deshalb kontrollierte Gewinnung auf verschiedenen Ebenen:• Vermehrung
• Homozygotes Saatgut oder Klonpflanzen von auf optimalen Wirkstoffgehalt gezüchteten Pflanzen,
• Anbau• optimierte und beeinflußbare Kulturbedingungen
Pflanzenmaterial
Dr. Markus Veit
Anbau: Petasites hybridus
Dr. Markus Veit
Primärverarbeitung / Lagerung /Transport
Waschen, zerkleinern,Trocknung im Freien, Verunreinigung durch Staub, Haustiere, Ungeziefer
geeignetes Verpackungsmaterial,geeignete Lagerungsbedingungen
Folie Dr. Stolte
Dr. Markus Veit
GMP Good Manufacturing Practice
→ EUDRALEX: Volume 4 Medicinal Products for Human and Veterinary Use; speziell im Annex 7: Manufacture of Herbal Medicinal Products
Richtlinien zur Qualitätssicherung der Produktionsabläufe / -umgebung
→ Gewährleistung der Anforderungen an Qualität und Reinheit der Wirkstoffe, welche sie zu besitzen vorgeben oder laut Deklaration besitzen sollen
Qualitäts-Sicherungssysteme (1)
Aber:bei pflanzlichen Arzneimitteln fällt Anbau / Ernte / Trockung /Lagerung nicht unter die GMP-Regelungen, daher wurden „eigene“ weitere Qualitätskriterien dafür erstellt
→ → → → → → → → → → → → → → → → GACPFolie Dr. Stolte
Dr. Markus Veit
Qualitäts-Sicherungssysteme (2)GACP Good Agricultural and Collection Practice (GACP) for Starting Materials of Herbal Origin (EMEA/HMPC/246816/2005)
→ Qualitätssicherungssystem für die Wildsammlung und / oder den Anbau, die Ernte und die ersten Verarbeitungsschritte
keine „GMP-Guideline“ im eigentlichen Sinne Grundlage zur Etablierung eines entsprechenden Qualitätssicherungssystems
- hygienische Produktion (mikrobielle Belastung auf ein Minimum reduzieren)
- vorsichtige Behandlung (keine nachteilige Beeinflussung während Sammlung / Anbau, Bearbeitung, Lagerung)
Folie Dr. Stolte
Dr. Markus Veit
Pflanze
SammlungAnbau/ Ernte
LagerungPrimärverarbeitung
ZerkleinerungExtraktionReinigung
DarreichungsformVerpackung/Beschriftung
Stabilität
Good Agricultural and Collection
Practice (GACP)
GMP (Produkt)
GMP Ausgangsmaterial
GACP/GMP Spezifikation
Qualitätskontrolle
/ PrüfungInform
ation /
Dokum
entation
Grenzen zwischen GACP und GMP sind fließend
Folie Dr. Stolte
Dr. Markus Veit
Information on the Drug considering the GACP Guidelines Identification Name of the herbal drug Code No. Contract-No.Origin Origin of herbal drug Cultivated or Collected from wild growing plants Country / Region / one area /
different areasAgricultural information Information on the kind of soil Information on the surroundingsTreatments on the harvested raw material Treatment before and during harvesting Treatment directly after harvesting Treatment of drug between harvesting and storage Drying (natural / artificial drying) …
Dr. Markus Veit
Information on the Drug considering the GAP Guidelines
…
Storage conditionsTransportation
Treatment before or during the transportation (methyl bromide, phosphorous hydrogen, ethylene oxide, ionizing radiation...)
Others Is the plant material gene manipulated? (GMO)
Tests performed by the supplier in the plant material (loss on drying...)
Supplier’s assurance of future deliveries with the same quality
Dr. Markus Veit
3.2.S.2.2 Description of Manufacturing Process and Process Controls For herbal substancesInformation should be provided to adequately describe the plant
production and plant collection, including:- Geographical source of medicinal plant- Cultivation, harvesting, drying and storage conditions- Batch size
For herbal preparations Information should be provided to adequately describe the
manufacturing process of the herbal preparation, including:- Description of processing (including flow diagram)- Solvents, reagents
3.2.S. DRUG SUBSTANCE/DRUG PREPARATION
Dr. Markus Veit
Process control → Standardization (1) Definition of all types material used Initial plant material (taxon, seed, clone material...)
Harvested plant material (organ, developmental stage, constituents, contaminants, ...)
Starting material (particle size, water content, shelf live, constituents, contaminants, ...)
Extract (particle size, water content, shelf live, constituents, contaminants, ...)
(1a) Definition of all types chemicals used Agrochemicals
Extraction solvents
Excipients
Dr. Markus Veit
(2) Identification of each step of the process and establishment of critical parameters for each step
Cultivation
Harvest
Drying
Milling
Blending
Extraction
Blending
Production of finished product (Unit dosing)
Packaging and storage
Process control → Standardization
Dr. Markus Veit
Droge
AnlagenHerstellverfahren
Extrakt
Auszugsmittelart
Auszugsmittel-konzentration
AuszugsmittelmengeDurchfluß-geschwindigkeit
Füllmenge
Füllhöhe(Fülldichte)
Statischer DruckChargengrößeExtraktionsdruck
Extraktionstemperatur
ExtraktionszeitExtraktionsart
Homogenität
Pulveranteil
SchnittgrößeWassergehalt
Extraktivstoffgehalt Auszugsmittel
Abhängigkeit der Menge und Zusammensetzung von Extrakten von Herstell- und Qualitätsparametern [nach Gaedcke]
Dr. Markus Veit
Dr. Markus Veit
Table of contents
1. Composition / weight2. Extraction3. Filtration4. Concentration5. Addition of excipients6. Drying7. Standardisation8. Milling9. Homogenisations10. Granulation 11. Packing
3.2.S.2.2 Description of Manufacturing Process and Process Controls
Dr. Markus Veit
3.2.S.2.3 Control of Materials 3.2.S.2.4 Controls of Critical Steps and Intermediates 3.2.S.2.5 Process Validation and/or Evaluation
3.2.S.2.6 Manufacturing Process Development A brief summary describing the development of the herbal
substance(s) and herbal preparation(s) where applicable should be provided, taking into consideration the proposed route of administration and usage. Results comparing the phytochemical composition of the herbal substance(s) and herbal preparation(s) where applicable used in supporting bibliographic data and the herbal substance(s) and herbal preparation(s) where applicable described in S.1 should be discussed, where appropriate.
3.2.S. DRUG SUBSTANCE/DRUG PREPARATION
Dr. Markus Veit
3.2.S.2.6 Manufacturing process development Brief summary describing the development of the herbal
substance(s) and herbal preparation(s), taking into consideration the proposed route of administration and usage.
• Product Definition and classification according to Ph. Eur.
• Used Raw Material. Justification of any deviation from the
official monographs or any additional specification required
• Used Extraction Solvent
• Manufacturing procedure. Justification of the different steps
and IPCs
3.2.S. DRUG SUBSTANCE/DRUG PREPARATION
Dr. Markus Veit
3.2.S. DRUG SUBSTANCE/DRUG PREPARATION
3.2.S.3 Characterisation
3.2.S.3.1 Elucidation of Structure and other Characteristics For herbal substances Information on the botanical, macroscopical, microscopical,
phytochemical characterisation, and biological activity if necessary, should be provided.
For herbal preparationsInformation on the phyto- and physicochemical characterisation,
and biological activity if necessary, should be provided.
3.2.S.3.2 Impurities
Dr. Markus Veit
Information on impurities in the herbal substance(s) and herbal preparation(s).
• Contaminants coming from the herbal substance
• Contaminants from the manufacturing process
3.2.S.3.2 Impurities
Dr. Markus Veit
CPMP/QWP/2820/00 Rev 1: Impurities
Impurities can be classified as follows:• impurities arising from starting materials (active substances,
excipients) and containers;• process related impurities arising from the manufacturing process.
In addition, for herbal medicinal products the following groups of impurities should be addressed, if appropriate:
Contaminants, which are impurities such as heavy metals, pesticides, mycotoxins, fumigants as well as microbial contamination, including those arising from extraneous sources, and radioactive substances, if relevant.
Degradation products, due to the particular nature of herbal medicinal product, should primarily address toxicologically relevant impurities arising from degradation of herbal substances/preparations.
Residual solvents, which are impurities arising from manufacturing processes.
Dr. Markus Veit
Mycotoxins (Aflatoxins)
Heavy Metals
Pesticides (and Fumigants)
Microbiological Quality
Residual Solvents
Radioactive Contamination
Other contaminants- Dioxines- PAHs- "Residues" of Food Irradiation
3.2.S.3.2 Impurities
Dr. Markus Veit
Aflatoxine
Ph. Eur. Monographie „Pflanzliche Drogen“ …Falls erforderlich können Grenzwerte für Aflatoxine gefordert werden. …
Ph. Eur. Monogr. „Best. von Aflatoxin B1 in pflanz. Drogen“ 2.8.18 Pflanzliche Drogen, die durch Aflatoxine kontaminiert sein können, müssen mit einer validierten Methode geprüft werden. Wenn in der Einzelmonographie nichts anderes vorgeschrieben ist, dürfen pflanzliche Drogen höchstens 2 µg Aflatoxin B1 je Kilogramm enthalten. Die zuständige Behörde kann auch für den Gesamtgehalt an Aflatoxin B1, B2, G1 und G2 einen Grenzwert von 4 µg je Kilogramm pflanzliche Droge festlegen.
Folie Dr. Stolte
Dr. Markus Veit
Aflatoxine
Aflatoxin VerbotsV, (BGBl. Teil I, Nr. 33, 25. Juli 2000) :
Aflatoxin M1: 0,05 µg/kgAflatoxin B1: 2,00 µg/kgGesamtmenge der Aflatoxin B1, B2, G1, G2: 4,00 µg/kg
§1 Es ist verboten bei der Herstellung von Arzneimitteln Stoffe zu verwenden, deren Höchstmenge an Aflatoxinen … überschritten wird.
§2 Das Inverkehrbringen eines Arzneimittels, das entgegen §1 hergestellt worden ist, ist verboten….
Als Verordnung direkt geltendes Recht
Folie Dr. Stolte
Aflatoxin B1 Aflatoxin B2 Aflatoxin G1 Aflatoxin G2
Dr. Markus Veit
Heavy Metals – Ph. Eur. (Herbal Drugs
Pb: 5 mg/kg, Cd: 1,0 mg/kg und Hg: 0,1 mg/kg
Dr. Markus Veit
Pesticides - Legal requirements
European Pharmacopoeia: "2.8.13. Pesticide Residues" gives a definition and determines maximum residues limits for pesticides in pharmaceuticals; describes a method (sampling, reagents, apparatus) for testing pesticides (but method not mandatory!)
Dr. Markus Veit
Keimreduzierungsverfahren
Waschen → ! Qualität des Wassers ist wichtig ! Pasteurisieren / Sterilisieren (z.B. Dampf, Hitze)
Begasung → Ethylenoxid in Deutschland verboten, andere Mittel (PH3, CH3Br, SO2, CO2) erlaubt, RHmV beachten
ionisierende Strahlen → erfordert eigene Zulassung
Alkohole → bei der Extraktion
Folie Dr. Stolte
Dr. Markus Veit
Dr. Markus Veit
EMEA/HMPC/125562/2006
PROBLEM STATEMENT
The use of ethylene oxide for the decontamination of herbal substances is prohibited in Europe2 since 31 December 1989.
In addition, manufacturers and applicants need to be aware that the use of methyl bromide, one of the most widely used fumigants, is currently being phased out worldwide in accordance with the Montreal Protocol 1992 because it is an ozone depleting substance.
As such manufacturers and applicants will need to consider alternative strategies for pest control of herbal substances used in herbal medicinal products.
Dr. Markus Veit
Fumigants - Legal Requirements
Foodstuffs (Germany):Regulation of maximum residue limits of pesticides in foodstuffs
[Rückstands-Höchstmengenverordnung (RHmV) i.d.F. der 14. ÄndV vom 7.4.2006]
- Ethylene oxide: 0,10 mg/kg - Methyl Bromide calculated as anorganic Bromide: max. 50 mg/kg (spices: 400 mg/kg chamomile: 150 mg/kg, mate leaves, hibiscus flowers: 100 mg/kg)- Phosphine: 0,01 mg/kg
Dr. Markus Veit
Residual Solvents - Legal Requirements European Pharmacopoeia: „5.4. Residual Solvents“ Limiting Residual Solvent Levels in Active Substances, Excipients and Medicinal Products
Based on „CPMP/ICH/283/95: Impurities: Guidelines for Residual Solvents“
Class 1 solvents: Solvents to be avoided Known human carcinogens, strongly suspected human carcinogens, and environmental hazards
Class 2 solvents: Solvents to be limited Non genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as
neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities.
Class 3 solvents: Solvents with low toxic potential Solvents with low toxic potential to man; no heath-based exposure limit is needed. Class 3 solvents have PDE (permitted daily exposure) of 50 mg or more per day.
(Solvents for which no adequate toxicological data were found)
Dr. Markus Veit
Residual Solvents - Some samples
Class 1 solvents: Solvents to be avoided Benzene, Carbon tetrachloride, 1,2 Dichlorethane, 1,1-Dichlorethane, 1,1,1-Trichlorethane
Class 2 solvents: Solvents to be limited Solvent PDE (mg/day) Limit (mg/kg) Cyclohexane 35,8 3880 Dichloromethane 6,0 600 Ethylen glycol 3,1 310 Hexane 2,9 290 Methanol 30,0 3000
Class 3 solvents: Solvents with low toxic potential Acetic acid, Acetone, 1-Butanol, Dimethylsulfoxide, Ethanol, Ethylacetate, Heptane, Pentane, 1-Propanol, 2-Propanol
Solvents for which no adequate toxicological data were found Isooctane, Isopropyl ether, Petroleum ether, Trifluoroacetic acid, Trichloroacetic acid
Dr. Markus Veit
Radioactive Contamination
EC directive 737/90/EWG (22.3.1990):Max. cumulated radioactivity of Caesium 134 and 137 in:• milk, milk products and
nutrition for babies: 370 Bq/kg• other products: 600 Bq/kg• Herbal Drugs:
„In some specific circumstances, the risk of radioaktive contamination is to be considered“
Dr. Markus Veit
Other „Contaminants“
Dioxines
PAHs
„Residues“ of Food Irradiation
Dr. Markus Veit
Mikrobiologie: Harmonisierung der Anforderungen
Für pflanzliche Arzneimittel konnte keine Harmonisierung der Anforderungen zwischen der USP, dem Japanischen Arzneibuch und dem Ph.Eur. erzielt werden.
Ursache: in USA und Australien (Lieferant für Japan) wird Ethylenoxidbegasung als Keimreduzierung akzeptiert, daher in der Regel niedrigere Grenzwerte möglich
Konsequenz: für pflanzliche Drogen / Zubereitungen / Arzneimittel werden im Ph. Eur. eigene Grenzwerte festgelegt
Folie Dr. Stolte
Dr. Markus Veit
European Pharmacopoeia: Chapter 5.1.8 (6.7, valid 4/2010)
- Category A:Herbal medicinal products containing herbal drugs, with or without excipients, intended fort he preparation of infusions and decoctions using boiling water (for example herbal teas, with or without added flavourings
- Category B:Herbal medicinal products containing, for example, extracts and/or herbal drugs, with or without excipients, where it can be demonstrated that the method of processing (for example, extraction) or, where appropriate, in the case of herbal drugs, of pre-treatment reduces the level of organisms to below those stated for this category
- Category C:Herbal medicinal products containing, for example, extracts and/or herbal drugs, with or without excipients, where it can be demonstrated that the method of processing (for example, extraction with low strength ethanol or water that is not boiling or low temperature concentration) or, in the case of herbal drugs, of pre-treatment, would not reduce the level of organisms sufficiently to reach the criteria required under B
3.2.S.3.2 Impurities: Microbiological Quality
Dr. Markus Veit
3.2.S. DRUG SUBSTANCE/DRUG PREPARATION3.2.S.4 Control of Drug Substance Data for herbal substance(s) and herbal preparations
should be provided.3.2.S.4.1 Specification 3.2.S.4.2 Analytical Procedures 3.2.S.4.3 Validation of Analytical Procedures 3.2.S.4.4 Batch Analyses 3.2.S.4.5 Justification of Specification
Dr. Markus Veit
Dr. Markus Veit
CPMP/QWP/2820/00 Rev 1
A specification is defined as a list of tests, references to analytical or biological procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described.It establishes the set of criteria to which a herbal substance, herbal preparation and herbal medicinal product should conform to be considered acceptable for its intended use. "Conformance to specifications“ means that the herbal substance/preparation and/or herbal medicinal product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are legally binding quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.
Dr. Markus Veit
Typen von Akzeptanzkriterien
• Dichotome Akzeptanzkriterien (ja/nein)• Ja/Nein
- Identität, Aussehen, Grenzwertprüfungen für die Reinheit (< NWG, nmt (≤) _,_ %)
• Metrische Akzeptanzkriterien für Mittelwerte• Numerische Ergebnisse
- Gehalt (_,_ %), Reinheit (_._ %), Wassergehalt (_,_ %), Bruchfestigkeit (_ N), Masse (_mg)
• Akzeptanzregeln der Ph.Eur.• Ja/Nein für Regel für Mittelwerte, Einzelwerte und Streuung
- Wirkstofffreisetzung (S1[6], S2[12], S3[24])- Gleichförmigkeit (L1[10], L2[30])- Teilbarkeit von Tabletten (30 Einzelwert-Betrachtungen)
Folie Dr. Limberg
Dr. Markus Veit
CPMP/QWP/2820/00 Rev 1
It is possible that, in addition to release tests, a specification may list in-process tests, periodic (skip) tests, and other tests, which are not always conducted on a batch-by-batch basis. In such cases the applicant should specify which tests are routinely conducted batch-by-batch, and which tests are not, with an indication and justification of the actual testing frequency. In this situation, the herbal substance/preparation and/or herbal medicinal product should meet the acceptance criteria if tested.It should be noted that changes in the specification after approval of the application will need prior approval by the regulatory authority.
Dr. Markus Veit
• Ist möglich• Definition über Menge oder Zeit oder …• Es muss plausibel sein, dass die nicht
geprüften Chargen der Spezifikation entsprechen
• Genehmigung (Approval) erforderlich• Erst wenn genug Daten vorliegen• Bei Abweichungen zurück zur Routineprüfung
ICH Q6A: Skip Testing
Dr. Markus Veit
ICH Q6A: Inprozesskontrolle
… sind normalerweise nicht Bestandteil der Spezifikation,
… können aber in die Spezifikation aufgenommen werden. Validierung/Argumentation nötig, dass der nachfolgende Herstellprozess das Ergebnis nicht beeinflusst
Dr. Markus Veit
Prüfverfahren
• Zur Spezifikation gehört die Angabe des Prüfverfahrens (hausinterne Bezeichnung ABCxxx) oder Bezug auf Arzneibuch
• Das Prüfverfahren muss so beschrieben werden, dass Fachleute es reproduzieren können (detaillierte Angaben, aber keine SOP)
• Das Prüfverfahren muss validiert sein, d.h. es muss belegt werden, dass dieses Prüfverfahren für das zu untersuchende Qualitätsmerkmal an dem speziellen Produkt geeignet ist.
Folie Dr. Limberg
Dr. Markus Veit
a) Definition: a qualitative statement of the botanical source, plant part used and its state (e.g. whole, reduced, powdered, fresh, dry). It is also important to know the geographical source(s) and the conditions under which the herbal drug is obtained.
b) Characters: a qualitative statement about the organoleptic character(s) where characteristic and the macroscopic and microscopic botanical characters of the herbal drug.
c) Identification: identification testing optimally should be able to discriminate between related species and/or potential adulterants/ substitutes, which are likely to be present.
Macroscopical characters
Microscopical characters
Chromatographic procedures (TLC, HPLC, GC Fingerprints)
Genetic fingerprints
Specifications for Herbal Drugs II
Dr. Markus Veit
1: V. officinalis
2: V. edulis
3: V. wallichii
4: Extr. Valerianae
1 2 3 4
Differentiation of Valeriana species
Dr. Markus Veit
TLC fingerprints of Hypericum German versus Chinese crude drug origins
1. Crude drug acc. to DAC2. Chinese origin3. Reference compounds4. Extract German crude drug5. Extract Chinese crude drug
plant material extract
Dr. Markus Veit
Echinacea - Fingerprints
HPLC separation of caffeic acid derivatives from the overground parts of Echinacea species.
1 = 2-caffeoyl tartaric acid,
2 = chlorogenic acid,
3 = cichoric acid,
4 = isomer of cichoric acid,
5 = cichoric acid monomethylester,
6 = echinacoside,
7 = rutin,
8 = verbascoside,
9 and 10 = isochlorogenic acids,
11 = unknown caffeic acid derivative.
From BAUER & WAGNER 1990
Dr. Markus Veit
Specifications for Herbal Drugs III
d) Tests Foreign matter Total Ash Ash Insoluble in hydrochloric acid Water soluble extractive Extractable matter Particle size Water content Microbial limits Other appropriate tests (e.g. swelling index)
Radioactive isotopes
Dr. Markus Veit
e) assays markers active constituents (Myco)toxins Pesticides, Fumigation agents, etc. Inorganic impurities, toxic metals
Specifications for Herbal Drugs IV
Dr. Markus Veit
GC-MS of Valerian extract
Dr. Markus Veit
Identification of the peaks at 16.47 min as bornylacetate
etc.
Dr. Markus Veit
Verwendung von Leitsubstanzen zu Kontrollzwecken….
• Lagerung• Prozess• Identitätsprüfung• Analytisches Verfahren• chargenspezifische Kontrolle• … individuelle Zwecke
Dr. Markus Veit
Auswahlkriterien von Leitsubstanzen
Dr. Markus Veit
Auswahlkriterien von Leitsubstanzen
• (Selektives) Vorkommen• Stabilität• Analytisches Verhalten
• verfahrensbezogene Stabilität • Löslichkeit• Selektive Bestimmung (in Gegenwart von
Matrix)• Analytisches Verfahren• Beschreibung im Arzneibuch Cave
Dr. Markus Veit
Leitsubstanzen mit therapeutischem Bezug
• Matricin und Bisabolole in Kamillenblüten
• Thymol in Thymianblättern• Sesquiterpenlaktone Arnikablüten• Bitterstoffe in Entianwurzel• einzelne Saponine in vers. Drogen• …
Dr. Markus Veit
Leitsubstanzen für Drogen Ph. Eur
• Qualitätsbestimmend • Acteosid in Spitzwegerichblättern (Mindestwert)• Anethol und Fenchon in Fenchelfüchten (Spanne)• Flavonoidglykoside in vers. Droge (Mindestwert/Spanne)
• Identitätsbestimmend• Leiocarposid in Echter Goldrute • Valerensäure in offizieneller Baldrianwurzel
• Nicht Qualitäts-/Identitätsbestimmend• Scopoletin in Brennnesselwurzel
Dr. Markus Veit
Beispiel Acteosid I
Bei Acteosid handelt es sich um ein phenlyethanoides Glucorhamnosid das mit einer Kaffeesäure verestert vorliegt. Die Substanz ist bei den Lamiales im Pflanzenreich weit verbreitet. Sie kommt in allen Organen innerhalb der Gattung Plantago vor. In schlecht getrockneter und/oder falsch gelagerter und/oder alter Droge baut die Substanz ab bzw. wird mikrobiell abgebaut.
Qualitätsmerkmal für die Droge
Dr. Markus Veit
Anforderungsprofil Leitsubstanzen
• Arzneibuch• wertbestimmend (sollte ausreichend stabil sein)• qualitätsbestimmend (sollte hinreichend instabil sein)
• Chargenbezogene Prüfung• analytisch gut bestimmbar & stabil
• Prozesskontrolle• für den individuellen Zweck geeignet
Dr. Markus Veit
a) Definition: a statement of the botanical source, and the type of preparation (e.g. dry or liquid extract). The ratio of the herbal drug to the herbal drug preparation must be stated.
b) Characters: a qualitative statement about the organoleptic characters of the herbal drug preparation where characteristic
c) Identification: Identification tests should be specific for the herbal drug preparation, and optimally should be discriminatory with regard to substitutes/adulterants that are likely to occur.
•Chromatographic procedures (TLC, HPLC, GC Fingerprints)
Specifications for Herbal Drugs Preparations II
Dr. Markus Veit
d) Tests Microbial limits
e) Assays
markers active constituents Residual solvents Water content Inorganic impurities, toxic metals Mycotoxins: Pesticides, Fumigation agents, etc.
Specifications for Herbal Drugs Preparations III
Dr. Markus Veit
Chargenkonformität
Dr. Markus Veit
0
0,350
0,700
1,050
1,400
flavone glycosid
es
ginkgolides A, B
, C
bilobalide
terpene lactones
Con
tent
[%]
560656075608591059116087858686778705
Variation of different batches of Ginkgo biloba leaves
Dr. Markus Veit
0
7,50
15,00
22,50
30,00
flavone glycosid
es
ginkgolides A, B
, C
bilobalide
terpene lactones
876877878879880881882883884885886
Variation of different batches of Ginkgo biloba extract EGb 761
Dr. Markus Veit
3.2.S.4.2 Analytical procedures
Information on analytical procedures used for testing the
herbal substance(s) or herbal preparation(s).
3.2.S.4.3 Validation of Analytical procedures
Analytical validation information, including experimental
data for the analytical procedures used for testing the
herbal substance(s) or herbal preparation(s).
3.2.S. DRUG SUBSTANCE/DRUG PREPARATION
Dr. Markus Veit
3.2.S.4.4 Batch analyses
Description of batches and result of batch analyses
3.2.S.4.5 Justification of specification
Justification for the drug the herbal substance(s) or herbal
preparation(s) specification
3.2.S. DRUG SUBSTANCE/DRUG PREPARATION
Dr. Markus Veit
Justification of specifications
The setting of specifications for a herbal substance/preparation and herbal medicinal product is part of an overall control strategy which includes control of raw materials and excipients, in-process testing, process evaluation/validation, stability testing and testing for consistency of batches. When combined in total, these elements provide assurance that the appropriate quality of the product will be maintained. Since specifications are chosen to confirm the quality rather than to characterise the product, the manufacturer should provide the rationale and justification for including and/or excluding testing for specific quality attributes. The following points should be taken into consideration when establishing scientifically justifiable specifications.
Dr. Markus Veit
Begründung von Spezifikationen
• Entwicklung & Scale up Pharmazeutische Entwicklung• Stabilitätsstudien• Funktionalitätsstudien• Validierung (Prozess & Analytik)• Arzneibuch• Guidelines • Präklinische/Klinische Chargen• Marktchargen• Metabolismus• Wissenschaftliche Literatur• Statistik / Massenbilanz
Dr. Markus Veit
3.2.S.5 Reference Standards or Materials
• Botanische Standards (Herbarbelege)
• Drogenstandard / Zubereitungsstandards
• Wirksamkeitsbestimmende Inhaltsstoffe
• Leitsubstanzen (analytical/active Marker)
• Konservierungsmittel/Antioxidantien
• Alkohol
• Verunreinigungen
• Restlösemittel
• Mykotoxine
• …
Arzneibuch-Standards müssen nicht näher beschrieben werden
Dr. Markus Veit
1. IDENTITY TESTS 1.1. General information 1.2. UV Spectroscopy 1.3. TLC Identity 1.4. 1H-NMR Spectroscopy2. PURITY DETERMINATION 2.1. HPLC-DAD purity determination 2.2. TLC purity evaluation 2.3. 1H-NMR purity determination 2.4. Residual solvents out of production 2.5. Water content3. CONTENT DETERMINATION 3.1. HPLC content determination 3.2. 1H-NMR content determination 3.3. Conclusion4. BIBLIOGRAPHY5. CERTIFICATE OF ANALYSIS
REFERENCE STANDARD RS IDENTITY TEST, PURITY AND QUANTITATIVE DETERMINATION
3.2.S.5 Reference Standards or Materials
Dr. Markus Veit
• Description of the container closure system.• Discussion with respect to the choice of materials , protection from
moisture and light, compatibility and safety.Primary Packaging Material
• Identity of materials of construction
• Specifications (description, identification, dimensions)
• Methods (validations)
Secondary Packaging Material
• For non-functional: a brief description
• For functional: additional information
3.2.S.6 Container Closure System
Dr. Markus Veit
3.2.S.7.1 Stability summary and conclusions
Summary of:• Types of studies conducted • Used protocols• Results
3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment
Commitment to continue the stability studies, to firmly establish the re-test period, when the available long term stability data on primary batches does not cover the proposed re-test period at the time of approval.
3.2.S.7.3 Stability Data
• Results of the stability studies in appropriate format (tabular, graphical or narrative)• Information on the analytical methods, and their validations
3.2.S.7 Stability
Dr. Markus Veit
Stability testing of HMPs
Dr. Markus Veit
CPMP/QWP/2819/00 Rev 1 .
Since the herbal substance or herbal preparation in its entirety is regarded as the active substance, a mere determination of the stability of the constituents with known therapeutic activity will not suffice. The stability of other substances present in the herbal substance or in the herbal preparation, should, as far as possible, also be demonstrated, e.g., by means of appropriate fingerprint chromatograms. It should also be demonstrated that their proportional content remains comparable to the initial fingerprint.
Dr. Markus Veit
CPMP/QWP/2819/00 Rev 1 .
In the case of a herbal medicinal product containing a herbal substance or herbal preparation with constituents of known therapeutic activity, the variation in content during the proposed shelf-lifec should not exceed ± 5% of the declared assay value, unless justified. In the case of a herbal medicinal product containing a herbal substance or herbal preparation where constituents with known therapeutic activity are unknown, a variation in marker content during the proposed shelf-life of ±10% of the initial assay value can be accepted if justified by the applicant.
Dr. Markus Veit
1. Introduction / Overview 2. Storage conditions 3. Tested parameters 4. Legislation, regulations and guidelines5. Batch results6. Discussion of results7. Conclusion 8. Stability graphics / figures9. Enclosures (TLC and HPLC chromatograms)
STABILITY REPORT
3.2.S.7.3 Stability data
Dr. Markus Veit
—— 25°C/60% HR—— 30°C/65% HR—— 40°C/75% HR
3.2.S.7.3 Stability data
Dr. Markus Veit
Initial
3 months 30ºC / 65% rh
3 months 25ºC / 60% rh
3 months 40ºC / 75% rh
6 months 30ºC / 65% rh
6 months 25ºC / 60% rh
6 months 40ºC / 75% rh
9 months 30ºC / 65% rh
9 months 25ºC / 60% rh
STABILITY REPORTS: Batch results
Dr. Markus VeitFolie Gaedcke
Dr. Markus Veit
Stabilitätsuntersuchungen: Fingerprint
