3.2.S. DRUG SUBSTANCE/DRUG PREPARATION

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

3.2.S. 1 General Information 3.2.S.1.1 Nomenclature

Information 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

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

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

Produktion Pflanzlicher Arzneimittel

frische Pflanzen Drogen (getrocknet)

Presssäfte

selten Extrakte

Arzneitees

Drogen-Pulver Extrakte

Fertigarzneimittel in verschiedenen

Darreichungsformen und Anwendungsarten Trocknung

Lagerung Verpackung Transport An

ba u/ Er nt e

Anbau oder Wildsammlung

Unkontrollierte Bedingungen Kontrollierte

Bedingungen

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

Anbau: Petasites hybridus

Primärverarbeitung / Lagerung /Transport

Waschen, zerkleinern,Trocknung im Freien,

Verunreinigung durch Staub, Haustiere, Ungeziefer

geeignetes Verpackungsmaterial, geeignete Lagerungsbedingungen

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

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)

Pflanze Sammlung Anbau/ Ernte

Lagerung

Primärverarbeitung Zerkleinerung

Extraktion Reinigung

Darreichungsform

Verpackung/Beschriftung Good Agricultural

and Collection Practice (GACP)

Ausgangsmaterial GMP GACP/GMP

Spezifikation Qualitätskontrolle / Prüfung Information / Dokumentation

Grenzen zwischen GACP und GMP sind fließend

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 areas

Agricultural information

Information on the kind of soil Information on the surroundings

Treatments 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)

…

Information on the Drug considering the GAP Guidelines

…

Storage conditions Transportation

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

3.2.S.2.2 Description of Manufacturing Process and Process Controls For herbal substances

Information 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

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

(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

Droge

Extrakt

Auszugsmittelart

Auszugsmittel- konzentration

Auszugsmittelmenge Durchfluß-

geschwindigkeit

Füllmenge Füllhöhe

(Fülldichte) Extraktionsdruck

Extraktionstemperatur Extraktionszeit

Extraktionsart Homogenität

Pulveranteil

Schnittgröße Wassergehalt

Extraktivstoffgehalt

Auszugsmittel

Abhängigkeit der Menge und Zusammensetzung von Extrakten

von Herstell- und Qualitätsparametern [nach Gaedcke]

Table of contents

1. Composition / weight 2. Extraction

3. Filtration

4. Concentration

5. Addition of excipients 6. Drying

7. Standardisation 8. Milling

9. Homogenisations 10. Granulation

11. Packing

3.2.S.2.2 Description of Manufacturing Process and Process Controls

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

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

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 preparations

Information on the phyto- and physicochemical characterisation, and biological activity if necessary, should be provided.

3.2.S.3.2 Impurities

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

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.

 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

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.

Aflatoxine

Aflatoxin VerbotsV, (BGBl. Teil I, Nr. 33, 25. Juli 2000) :

Aflatoxin M1: 0,05 µg/kg

Aflatoxin B1: 2,00 µg/kg

Gesamtmenge 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

Aflatoxin B1 Aflatoxin B2 Aflatoxin G1 Aflatoxin G2

Heavy Metals – Ph. Eur. (Herbal Drugs

Pb: 5 mg/kg, Cd: 1,0 mg/kg und Hg: 0,1 mg/kg

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!)

Keimreduzierungsverfahren

Waschen → ! Qualität des Wassers ist wichtig ! Pasteurisieren / Sterilisieren (z.B. Dampf, Hitze)

Begasung → Ethylenoxid in Deutschland verboten, andere Mittel (PH

₃

, CH

₃

Br , SO

₂

, CO

₂

) erlaubt, RHmV beachten

ionisierende Strahlen → erfordert eigene Zulassung

Alkohole → bei der Extraktion

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.

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

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.

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

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“

Other „Contaminants“

 Dioxines

 PAHs

 „Residues“ of Food Irradiation

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

 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

3.2.S.3.2 Impurities: Microbiological Quality

3.2.S. DRUG SUBSTANCE/DRUG PREPARATION

3.2.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

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.

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)

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.

• 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

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

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.

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

1: V. officinalis 2: V. edulis 3: V. wallichii

4: Extr. Valerianae

Differentiation of Valeriana species

TLC fingerprints of Hypericum

German versus Chinese crude drug origins

1. Crude drug acc. to DAC 2. Chinese origin

3. Reference compounds 4. Extract German crude drug 5. Extract Chinese crude drug

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.

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

e) assays

 markers

 active constituents

 (Myco)toxins

 Pesticides, Fumigation agents, etc.

 Inorganic impurities, toxic metals

Specifications for Herbal Drugs IV

GC-MS of Valerian extract

Identification of the peaks at 16.47 min as bornylacetate

etc.

Verwendung von Leitsubstanzen zu Kontrollzwecken….

• Lagerung

• Prozess

• Identitätsprüfung

• Analytisches Verfahren

• chargenspezifische Kontrolle

• … individuelle Zwecke

Auswahlkriterien von Leitsubstanzen

Auswahlkriterien von Leitsubstanzen

• (Selektives) Vorkommen

• Stabilität

• Analytisches Verhalten

• verfahrensbezogene Stabilität

• Löslichkeit

• Selektive Bestimmung (in Gegenwart von Matrix)

• Analytisches Verfahren

• Beschreibung im Arzneibuch  Cave

Leitsubstanzen mit therapeutischem Bezug

• Matricin und Bisabolole in Kamillenblüten

• Thymol in Thymianblättern

• Sesquiterpenlaktone Arnikablüten

• Bitterstoffe in Entianwurzel

• einzelne Saponine in vers. Drogen

• …

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

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

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

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

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

Chargenkonformität

0 0,350 0,700 1,050 1,400

A, B, C

bilobalide

Content [%]

56065607 56085910 59116087 85868677 8705

Variation of different batches of Ginkgo biloba leaves

0 7,50 15,00 22,50 30,00

A, B, C

bilobalide

876 877 878 879 880 881 882 883 884 885 886

Variation of different batches of

Ginkgo biloba extract EGb 761

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

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

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.

Begründung von Spezifikationen

• Entwicklung & Scale up Pharmazeutische Entwicklung

• Stabilitätsstudien

• Funktionalitätsstudien

• Validierung (Prozess & Analytik)

• Arzneibuch

• Guidelines

• Präklinische/Klinische Chargen

• Marktchargen

• Metabolismus

• Wissenschaftliche Literatur

• Statistik / Massenbilanz

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

1. IDENTITY TESTS

1.1. General information 1.2. UV Spectroscopy 1.3. TLC Identity

1.4. ¹H-NMR Spectroscopy 2. 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 content

3. CONTENT DETERMINATION 3.1. HPLC content determination 3.2. ¹H-NMR content determination 3.3. Conclusion

4. BIBLIOGRAPHY

REFERENCE STANDARD RS

IDENTITY TEST, PURITY AND QUANTITATIVE DETERMINATION

3.2.S.5 Reference Standards or Materials

• 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

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

3.2.S.7 Stability

Stability testing of HMPs

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.

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.

1. Introduction / Overview 2. Storage conditions

3. Tested parameters

4. Legislation, regulations and guidelines 5. Batch results

6. Discussion of results 7. Conclusion

8. Stability graphics / figures

9. Enclosures (TLC and HPLC chromatograms)

STABILITY REPORT

3.2.S.7.3 Stability data

—— 25°C/60% HR

—— 30°C/65% HR

—— 40°C/75% HR

3.2.S.7.3 Stability data

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

Stabilitätsuntersuchungen: Fingerprint