Implementation of GMP in the manufacturing of Herbal APIs (Extracts) Dr. Frank Waimer GA Workshop GACP/GMP Münster, 03/09/2013

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1 Implementation of GMP in the manufacturing of Herbal APIs (Extracts) Dr. Frank Waimer GA Workshop GACP/GMP Münster, 03/09/2013 1

2 EU-GMP Guideline Part II (since 2005) Transfer of ICH Q7A (2000) Detailed description of GMP requirements for active pharmaceutical ingredients Herbal API is especially mentioned. Special requirements (start of GMP requirements) are defined. 2

pharmaceutical ingredients Herbal API is especially

3 Scheme of the EU GMP- Guideline 3

4 GACP 4

5 GACP GACP regulates handling with medicinal plants during cultivation, collection, storage and Primary Processing (Cutting, Pressing, Distillation ) 5

6 Annex 7 The confusion begins Table illustrating the application of Good Practices to the manufacture of herbal medicinal products. Activity Collection, Cultivation and harvesting of plants, algae, fungi and lichens, and collection of exudates Cutting, and drying of plants, algae, fungi, lichens and exudates Expression from plants and Distillation * Comminution, processing of exudates, extraction from plants, fractionation, purification, concentration or fermentation of herbal substances Further processing into a dosage form including packaging as a medicinal product Good Agricultural and Collection Practice Part II of the GMP Guide Part I of the GMP Guide This table expands replaces in detail the herbal section of Table 1 in part II of the GMP Guide. 6

$from plants and Distillation * Comminution, processing of exudates, extraction from plants, fractionation, purification, concentration or fermentation of herbal substances Further processing$

7 Common Sense is needed The manufacturer should designate and document the rationale for the point at which production of the active substance begins. For synthetic processes, this is known as the point at which "Active Substance Starting Materials" are entered into the process. For other processes (e.g. fermentation, extraction, purification, etc.), this rationale should be established on a case-by-case basis. From this point on, appropriate GMP as defined in these guidelines should be applied to these intermediate and/or active substance manufacturing steps. Source: EU-GMP Part II 7

For other processes (e.g. fermentation, extraction, purification, etc.), this rationale should be established on a case-by-case basis.

8 Examples 8

9 4.12 Where the equipment itself (e.g., closed or contained systems) provides adequate protection of the material, such equipment can be located outdoors. 9

10 !!! 10

11 ??? 11

12 Realisation of Requirements Taking into account the particularities of the multitude of herbal preparations compliant concepts have to be found for: Zoning of production areas Validation/Qualification Documentation with special focus on the appropriateness for early process steps. 12

found for: Zoning of production areas Validation/Qualification

13 Room Concept GMP Requirements Pre Hygienic Zone Handling of Herbal Drug, Transfer to Extraction Pre Hygienic Zone Closed Systems for Purification, Concentration Hygienic Zone Drying, Milling, Blending Herbal API Collection of plants Cutting and initial extraction Further extraction Physical processing and packaging GMP 13

Concentration Hygienic Zone Drying, Milling, Blending Herbal API Collection of

14 Risk Based Approach for Qualification and Validation risk-based Herbal Drug Primary Extract Cutting, Extracting Requirements Purified Extract Spissated Purified Extract Purified Dry Extract Purification Concentrating Drying Milling full Standardised, Quantified Dry Extract, Purified 14 Standardising, Quantifying

Purified Extract Purified Dry Extract Purification Concentrating Drying

15 Formalised Risk Analysis Lfd. Nr. Prozessschritt / Anlagenteil Fehlerbeschreibung (Art und Ursache) 1 Anlagendesign Falsche Leitungsführung bei Umbauten durch Unkenntnis der bestehenden Leitungsführung denkbares Fehlverhalten / Auswirkung (Fehlerfolge) Kontamination des Produktes, Qualitätseinbußen RMM Aktuelles R+I- Schema TM 2 Einbau von nicht miteinander kompatiblen Anlagenkomponenten Ausfall von Anlagenkomponenten und dadurch bedingte Qualitätseinbußen Aktuelle Komponentenliste 3 Ungenügende Kenntnis über die vorhandenen Messstellen Negative Beeinflussung der Qualität des Produktes Aktuelle Messstellenliste 4 Verwendete Metalle (produktberührende) aus Edelstahl Entsprechen nicht den Anforderungen Negative Beeinflussung der Qualität des Produktes Materialzertifikate (FDA) und Nachweis über Lieferschein 5 Verwendete Kunststoffe (produktberührende) Entsprechen nicht den Anforderungen Negative Beeinflussung der Qualität des Produktes Materialzertifikate, Lebensmittelunbedenk lichkeitsbescheinigung, Nachweis über Lieferschein 15

Auswirkung (Fehlerfolge) Kontamination des Produktes, Qualitätseinbußen RMM Aktuelles R+I- Schema TM 2 Einbau von nicht miteinander kompatiblen Anlagenkomponenten Ausfall von Anlagenkomponenten und

16 Validation according to EU GMP Part II 1st Choice: prospective 2nd Choice: retrospective 3rd Choice: concurrent, but under defined preconditions: Modification within the process Lack of data from retrospective validation 16

concurrent, but under defined preconditions:

17 Documentation Complete Manufacturing and Testing Documentation Herbal Drug Primary Extract Purified Extract Spissated Purified Extract Purified Dry Extract Standardised, Quantifed Dry Extract, Purified Cutting, Extracting Purification Concentrating Drying Milling Standardising, Quantifying 17

Dry Extract Standardised, Quantifed Dry Extract, Purified Cutting,

18 Specifications for in-process solvents 18

19 Summary EU GMP Part II is mainly focussed on synthetical products Appropriate solutions have to be found for herbal preparations taking into account the particularities of the product and the process Border between GACP and GMP is flexible and approaches have to be developed on a case-by-case basis. 19

account the particularities of the product and the process Border between

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