3.2.S. DRUG SUBSTANCE/DRUG PREPARATION

Transkript

1 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

2 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 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 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

4 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.

5 Produktion Pflanzlicher Arzneimittel A n b a u / E r n t e frische Pflanzen Trocknung Drogen (getrocknet) Lagerung Verpackung Transport Arzneitees Drogen-Pulver Extrakte Presssäfte selten Extrakte Fertigarzneimittel in verschiedenen Darreichungsformen und Anwendungsarten Folie Dr. Stolte

6 Anbau oder Wildsammlung Kontrollierte Bedingungen Unkontrollierte Bedingungen Folie Dr. Stolte

7 Einheitliches Pflanzenmaterial kann aus Wildsammlungen nicht erhalten werden, deshalb kontrollierte Gewinnung auf verschiedenen Ebenen: Vermehrung Anbau Pflanzenmaterial Homozygotes Saatgut oder Klonpflanzen von auf optimalen Wirkstoffgehalt gezüchteten Pflanzen, optimierte und beeinflußbare Kulturbedingungen

8 Anbau: Petasites hybridus

9 Primärverarbeitung / Lagerung /Transport Waschen, zerkleinern,trocknung im Freien, Verunreinigung durch Staub, Haustiere, Ungeziefer geeignetes Verpackungsmaterial, geeignete Lagerungsbedingungen Folie Dr. Stolte

10 Qualitäts-Sicherungssysteme (1) 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 Aber:bei pflanzlichen Arzneimitteln fällt Anbau / Ernte / Trockung / Lagerung nicht unter die GMP-Regelungen, daher wurden eigene weitere Qualitätskriterien dafür erstellt Folie Dr. Stolte GACP

11 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

12 Grenzen zwischen GACP und GMP sind fließend Good Agricultural and Collection Practice (GACP) GACP/GMP GMP Ausgangsmaterial GMP (Produkt) Pflanze Sammlung Anbau/ Ernte Lagerung Primärverarbeitung Zerkleinerung Extraktion Reinigung Darreichungsform Verpackung/Beschriftung Stabilität Folie Dr. Stolte Spezifikation Dokumentation Information / Qualitätskontrolle / Prüfung

13 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)

14 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

15 3.2.S. DRUG SUBSTANCE/DRUG PREPARATION 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

16 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

17 Process control Standardization (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

18 Abhängigkeit der Menge und Zusammensetzung von Extrakten von Herstell- und Qualitätsparametern [nach Gaedcke] Droge Homogenität Extraktionsart Extraktionszeit Schnittgröße Pulveranteil Extraktivstoffgehalt Wassergehalt Extrakt Auszugsmittelart Auszugsmittel Auszugsmittelmenge Auszugsmittelkonzentration Durchflußgeschwindigkeit Füllmenge Extraktionstemperatur Extraktionsdruck Chargengröße Herstellverfahren Statischer Druck Füllhöhe (Fülldichte) Anlagen

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20 3.2.S.2.2 Description of Manufacturing Process and Process Controls 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

21 3.2.S. DRUG SUBSTANCE/DRUG PREPARATION 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.

22 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

23 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

24 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

25 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.

26 3.2.S.3.2 Impurities apple apple apple apple apple apple apple Mycotoxins (Aflatoxins) Heavy Metals Pesticides (and Fumigants) Microbiological Quality Residual Solvents Radioactive Contamination Other contaminants - Dioxines - PAHs - "Residues" of Food Irradiation

27 Aflatoxine Ph. Eur. Monographie Pflanzliche Drogen Falls erforderlich können Grenzwerte für Aflatoxine gefordert werden. Ph. Eur. Monogr. Best. von Aflatoxin B1 in pflanz. Drogen 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

28 Aflatoxine Aflatoxin B1 Aflatoxin B2 Aflatoxin G1 Aflatoxin G2 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 Folie Dr. Stolte

29 Heavy Metals Ph. Eur. (Herbal Drugs Pb: 5 mg/kg, Cd: 1,0 mg/kg und Hg: 0,1 mg/kg

30 Pesticides - Legal requirements apple European Pharmacopoeia: " 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!)

31 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 Folie Dr. Stolte

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33 EMEA/HMPC/125562/2006 PROBLEM STATEMENT The use of ethylene oxide for the decontamination of herbal substances is prohibited in Europe2 since 31 December 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.

34 Fumigants - Legal Requirements apple Foodstuffs (Germany): Regulation of maximum residue limits of pesticides in foodstuffs [Rückstands-Höchstmengenverordnung (RHmV) i.d.f. der 14. ÄndV vom ] - 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

35 Residual Solvents - Legal Requirements apple apple 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)

36 Residual Solvents - Some samples Class 1 solvents: Solvents to be avoided Benzene, Carbon tetrachloride, 1,2 Dichlorethane, 1,1-Dichlorethane, 1,1,1- Trichlorethane apple Class 2 solvents: Solvents to be limited Solvent PDE (mg/day) Limit (mg/kg) Cyclohexane 35, Dichloromethane 6,0 600 Ethylen glycol 3,1 310 Hexane 2,9 290 Methanol 30, apple apple 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

37 Radioactive Contamination EC directive 737/90/EWG ( ): 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

38 Other Contaminants apple Dioxines apple PAHs apple Residues of Food Irradiation

39 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

40 3.2.S.3.2 Impurities: Microbiological Quality apple European Pharmacopoeia: Chapter (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

41 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

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43 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.

44 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

45 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.

46 ICH Q6A: Skip Testing 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

47 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

48 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

49 Specifications for Herbal Drugs II 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

50 Differentiation of Valeriana species 1: V. officinalis 2: V. edulis 3: V. wallichii 4: Extr. Valerianae

51 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 plant material extract

52 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

53 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

54 Specifications for Herbal Drugs IV e) assays markers active constituents (Myco)toxins Pesticides, Fumigation agents, etc. Inorganic impurities, toxic metals

55 GC-MS of Valerian extract

56 Identification of the peaks at min as bornylacetate etc.

57 Verwendung von Leitsubstanzen zu Kontrollzwecken. Lagerung Prozess Identitätsprüfung Analytisches Verfahren chargenspezifische Kontrolle individuelle Zwecke

58 Auswahlkriterien von Leitsubstanzen

59 Auswahlkriterien von Leitsubstanzen (Selektives) Vorkommen Stabilität Analytisches Verhalten verfahrensbezogene Stabilität Löslichkeit Selektive Bestimmung (in Gegenwart von Matrix) Analytisches Verfahren Beschreibung im Arzneibuch Cave

60 Leitsubstanzen mit therapeutischem Bezug Matricin und Bisabolole in Kamillenblüten Thymol in Thymianblättern Sesquiterpenlaktone Arnikablüten Bitterstoffe in Entianwurzel einzelne Saponine in vers. Drogen

61 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

62 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

63 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

64 Specifications for Herbal Drugs Preparations II 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)

65 Specifications for Herbal Drugs Preparations III d) Tests Microbial limits e) Assays markers active constituents Residual solvents Water content Inorganic impurities, toxic metals Mycotoxins: Pesticides, Fumigation agents, etc.

66 Chargenkonformität

67 Variation of different batches of Ginkgo biloba leaves Content [%] 1,400 1,050 0,700 0, flavone glycosides ginkgolides A, B, C bilobalide terpene lactones

68 Variation of different batches of Ginkgo biloba extract EGb ,00 22,50 15, ,50 0 flavone glycosides ginkgolides A, B, C bilobalide terpene lactones

69 3.2.S. DRUG SUBSTANCE/DRUG PREPARATION 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).

70 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

71 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.

72 Begründung von Spezifikationen Entwicklung & Scale up Pharmazeutische Entwicklung Stabilitätsstudien Funktionalitätsstudien Validierung (Prozess & Analytik) Arzneibuch Guidelines Präklinische/Klinische Chargen Marktchargen Metabolismus Wissenschaftliche Literatur Statistik / Massenbilanz

73 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

74 3.2.S.5 Reference Standards or Materials REFERENCE STANDARD RS IDENTITY TEST, PURITY AND QUANTITATIVE DETERMINATION 1. IDENTITY TESTS 1.1. General information 1.2. UV Spectroscopy 1.3. TLC Identity H-NMR Spectroscopy 2. PURITY DETERMINATION 2.1. HPLC-DAD purity determination 2.2. TLC purity evaluation H-NMR purity determination 2.4. Residual solvents out of production 2.5. Water content 3. CONTENT DETERMINATION 3.1. HPLC content determination H-NMR content determination 3.3. Conclusion 4. BIBLIOGRAPHY 5. CERTIFICATE OF ANALYSIS

75 3.2.S.6 Container Closure System 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

76 3.2.S.7 Stability 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

77 Stability testing of HMPs

78 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.

79 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.

80 3.2.S.7.3 Stability data STABILITY REPORT 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)

81 3.2.S.7.3 Stability data 25 C/60% HR 30 C/65% HR 40 C/75% HR

82 STABILITY REPORTS: Batch results Initial 6 months 30ºC / 65% rh 3 months 30ºC / 65% rh 3 months 25ºC / 60% rh 3 months 40ºC / 75% rh 6 months 25ºC / 60% rh 6 months 40ºC / 75% rh 9 months 30ºC / 65% rh 9 months 25ºC / 60% rh

83 Folie Gaedcke

84 Stabilitätsuntersuchungen: Fingerprint