herbalmedicinalproducts: howtofillthectd correctly?€¦ · module 1 more information: presentation...
TRANSCRIPT
04.11.2014
1
Österreichische Agentur für Gesundheit und Ernährungssicherheit GmbHwww.basg.gv.at
Mag. Dr. Astrid ObmannExpert Group Herbal Medicinal Products & Homeopathics
Department Quality Assessment Medicinal Products
AGES-Gespräch „Herbal Medicinal Products and Homeopathics: an Update“
Vienna, 11.11.2014
Herbal Medicinal Products:How to fill the CTD correctly?
2
•CTD – General information
•Module 1 – Administrative information
•Modules 2, 4, 5 - Special requirements for
- Bibliographic applications
- Traditional herbal medicinal products (THMP)
•Module 3
•Concluding remarks
Outlook
04.11.2014
2
3
• http://ec.europa.eu/health/documents/eudralex/vol-2/index_en.htm
• Notice to Applicants Vol 2B –
Presentation and content of
the dossier
• THMP:
CTD – General information
4
Module 1
MRP/DCP:http://www.basg.gv.at/arzneimittel/formulare/mrp-dcp/http://ec.europa.eu/health/documents/eudralex/vol-2/index_en.htm
National procedures:http://www.basg.gv.at/arzneimittel/formulare/nationale-zulassung/
„Readability-Test“!
04.11.2014
3
5
• Bibliographic applications:
- Concise documentsummarizing the groundsand evidence for well-established use with an acceptable level of safetyand efficacy of the product
• THMP:
- Brief statement why theproduct meets therequirements of TUR
Module 1
More Information:Presentation „Update regardingPSUR and RMP for herbal andhomeopathic medicinal products“
6
• 2.3 QOS
- Short summary of relevant parts of module 3
• 2.4 Non-clinical Overview
- Bibliographic review ofsafety data
• 2.5 Clinical Overview
- Bibliographic review ofefficacy data
- Evidence on traditional use
Module 2
04.11.2014
4
7
•2.4 Non-clinical overview
- Bibliographic review of safety data
- Critical assessment of the pharmacologic, pharmacokineticand toxicological data
- If applicable, cross-reference to HMPC-Assessment report!
o CAVE:
� New relevant data, especially regarding safety, not alreadycontained in the HMPC-Assessment report should bediscussed
� In most cases only few data on genotoxicity are published, at least an AMES-Test according to current OECD-Guidelines isrequired!
� The respective studies should also be cross-referenced in thesummaries (2.6)
Module 2 - Bibliographic
8
•2.5 Clinical Overview
- Bibliographic review of efficacy data with respect togrounds for well-established use
- If applicable, cross-reference to HMPC-Assessment report!
- CAVE:
o If applicable, the relevance of new clinical data not alreadycontained in the HMPC-Assessment report should be discussedcritically!
o Be careful in the case of combination products!
•More information:
- Presentation „Requirements for the evidence of traditional use for THMP and for the evidence of efficacy forbibliographic applications“
Module 2 - Bibliographic
04.11.2014
5
9
• Literature references should beprovided in full text, if not already assessed by the HMPC
• If applicable, reports on additional safety data should beprovided
Module 4, 5 - Bibliographic
10
•2.4 Non-clinical overview
- Bibliographic review of safety data
- Critical Assessment of the pharmacologic, pharmacokineticand toxicological data
- If applicable, cross-reference to HMPC-Assessment report!
o CAVE:
� New relevant data, especially regarding safety, not alreadycontained in the HMPC Assessment Report should bediscussed
� Genotoxicity: at least an AMES-Test according to currentOECD-Guidelines with negative outcome is required.
� The list of relevant additional references can be included at the end of module 2.4
- „List Entry“ ? - No additional data required!
Module 2 - THMP
04.11.2014
6
11
•2.5 „Clinical overview“ - Evidence on traditional use
- Bibliographic or expert evidence that the product in question or corresponding product has been
o in medicinal use for at least 30 years preceding the date ofapplication
o including at least 15 years within the EU
- If applicable, cross-reference to HMPC-Monographs and „List Entries“! – No additional data required!
•More Information:
- Presentation „Requirements for the evidence of traditional use for THMP and for the evidence of efficacy forbibliographic applications“
Module 2 - THMP
12
•Module 4:
• Literature references regarding safety data should beprovided in full text, if not already assessed by theHMPC
•Module 5
• Usually not applicable
• Any relevant data should be provided in Module 2.7
•„List Entry“ ? – Module 4 and 5 are not required!
Module 4, 5 - THMP
04.11.2014
7
13
Module 3
14
Module 3
•3.2.S.2 Manufacture
- Complexity depends on type of herbal preparation
o Standardised, quantified, other extract?
o Justification of the DER?
o More than one step of extraction?
o Purification or partial separation of certain components?
o Complex procedures cannot be regarded as „standard procedure“!
� Process validation necessary (3.2.S.2.5)
� Information on process development required (3.2.S.2.6)
04.11.2014
8
15
•3.2.S.2 Manufacture
- Control of materials
o Guideline on GACP
o Could be difficult for certain preparations, e.g. essential oils
o All available documentation should be provided
o Specification of „starting material“ (herbal substance) should beincluded in 3.2.S.4.1
Module 3
16
•3.2.S.4 Control of drug substance
- Specification
o Herbal substance
� Specific Ph. Eur. monograph for the herbal substance?
� Mind also the general requirements of the Ph. Eur. monograph „Herbal drugs“!
� Impurities (heavy metals, aflatoxins, pesticide residues)
» Skip testing has to be justified by representativedata!
� Microbiological quality
» No specific requirements for the herbal substance, but usually conformity with Ph. Eur. chapter 5.1.8 A is requested
Module 3
04.11.2014
9
17
•3.2.S.4 Control of drug substance
- Herbal preparation
o Specific Ph. Eur. monograph for the herbal preparation (≠ herbalsubstance)?
o Analytical methods usually to be validated!
o Assay?
o Impurities (e.g. residual solvents)
o Mind the „guideline on specifications“!
Module 3
18
•3.2.P.2 Pharmaceutical development
- Complexity depends on the type of product, e.g.
o Single active substance or combination product?
o Pharmaceutical form?
o Route of administration?
o Paediatric formulation?
Module 3
Choice and function of excipients!Manufacturing process development„Analytical development?“Microbiological quality!
04.11.2014
10
19
•3.2.P.2 Pharmaceutical development
- Microbiological quality – antimicrobial preservation
o Product in multidose container
o Necessity of preservation should be demonstrated
o Choice and quantity of preservative agent should be justified
� Safety aspects
� Ph. Eur. 5.1.3 „Efficacy of antimicrobial preservation“
Module 3
20
•3.2.P.5 Control of Drug product
- Specification & Analytical Methods
o Mind the „guideline on specifications“!
o Mind the general requirements of the Ph. Eur. monograph „dosageforms“!
o Mind the (herbal) „guidelines on quality“!“
� Assay? Consider the decision trees in the guideline forcombination products!
� Analytical development?
� Validation of methods?
Module 3
04.11.2014
11
21
•3.2.P.7 Container closure system
- Plastic immediate packaging materials
o Complexity of required data depends on the dosage form
o Mind the decision trees in the respective guideline!
o Mind current provisions regarding compliance with Ph. Eur. or foodlaw!
Module 3
22
•3.2.P.8 Stability
- Generally CHMP/QWP guidelines are also valid for herbalmedicinal products
o European procedures: also data of intermediate and acceleratedstudies required
o National procedures: long-term studies as the minimumrequirement in combination with appropriate labelling
- In-use stability testing
o Products in multidose container
o General discussion, if shelf-life must be limited after first opening
o Test design and test storage conditions should reflect therecommendations proposed in the product information
Module 3
04.11.2014
12
23
•Especially in European Procedures:
- Stick strictly to the CTD-format
- Any „not applicable“ should be justified
•Take due account of scientific guidelines provided byHMPC/CHMP/QWP
•Cross-reference to HMPC-Assessment reportswhenever possible
Concluding remarks